4-phenylpiperidines, their preparation and use

ABSTRACT

The present invention provide a compound having the structure: (structurally represented) wherein R 1 , R 2 , R 3 , R 4 , and R 5  are each independently H, halogen, CF 3  or C 1 -C 4  alkyl; R 6  is H, OH, or halogen; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterocycle is other than chloro substituted indole; and the pyrazole, when substituted, is substituted with other than trifluoromethyl, or a pharmaceutically acceptable salt thereof.

This application is a divisional of U.S. application Ser. No.14/775,532, filed Sep. 11, 2015, which is a § 371 national stage of PCTInternational Application No. PCT/US2014/026813, filed Mar. 13, 2014,claiming the benefit of U.S. Provisional Application No. 61/785,187,filed Mar. 14, 2013, the contents of each of which are herebyincorporated by reference in their entirety.

The invention was made with government support under Grant numbersNS067594 and NS074476 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

Throughout this application, certain publications are referenced inparentheses. Full citations for these publications may be foundimmediately preceding the claims. The disclosures of these publicationsin their entireties are hereby incorporated by reference into thisapplication in order to describe more fully the state of the art towhich this invention relates.

BACKGROUND OF THE INVENTION

Age-related macular degeneration (AMD) is the leading cause of blindnessin developed countries. It is estimated that 62.9 million individualsworldwide have the most prevalent atrophic (dry) form of AMD; 8 millionof them are Americans. Due to increasing life expectancy and currentdemographics this number is expected to triple by 2020. There iscurrently no FDA-approved treatment for dry AMD. Given the lack oftreatment and high prevalence, development of drugs for dry AMD is ofupmost importance. Clinically, atrophic AMD represents a slowlyprogressing neurodegenerative disorder in which specialized neurons (rodand cone photoreceptors) die in the central part of the retina calledmacula (1). Histopathological and clinical imaging studies indicate thatphotoreceptor degeneration in dry AMD is triggered by abnormalities inthe retinal pigment epithelium (RPE) that lies beneath photoreceptorsand provides critical metabolic support to these light-sensing neuronalcells. Experimental and clinical data indicate that excessiveaccumulation of cytotoxic autofluorescent lipid-protein-retinoidaggregates (lipofuscin) in the RPE is a major trigger of dry AMD (2-9).In addition to AMD, dramatic accumulation of lipofuscin is the hallmarkof Stargardt Disease (STGD), an inherited form of juvenile-onset maculardegeneration. The major cytotoxic component of RPE lipofuscin ispyridinium bisretinoid A2E (FIG. 1). Additional cytotoxic bisretinoidsare isoA2E, atRAL di-PE, and A2-DHP-PE (40, 41). Formation of A2E andother lipofuscin bisretinoids, such as A2-DHP-PE(A2-dihydropyridine-phosphatidylethanolamine) and atRALdi-PE(all-trans-retinal dimer-phosphatidylethanolamine), begins inphotoreceptor cells in a non-enzymatic manner and can be considered as aby-product of the properly functioning visual cycle.

A2E is a product of condensation of all-trans retinaldehyde withphosphatidyl-ethanolamine which occurs in the retina in a non-enzymaticmanner and, as illustrated in FIG. 4, can be considered a by-product ofa properly functioning visual cycle (10). Light-induced isomerization of11-cis retinaldehyde to its all-trans form is the first step in asignaling cascade that mediates light perception. The visual cycle is achain of biochemical reactions that regenerate visual pigment (11-cisretinaldehyde conjugated to opsin) following exposure to light.

As cytotoxic bisretinoids are formed during the course of a normallyfunctioning visual cycle, partial pharmacological inhibition of thevisual cycle may represent a treatment strategy for dry AMD and otherdisorders characterized by excessive accumulation of lipofuscin (25-27,40, 41).

SUMMARY OF THE INVENTION

The present invention provides a compound having the structure:

-   -   wherein    -   R₁, R₂, R₃, R₄, and R₅ are each independently H, halogen, CF₃ or    -   C₁-C₄ alkyl;    -   R₆ is H, OH, or halogen    -   B is a substituted or unsubstituted heterobicycle, pyridazine,        pyrazole, pyrazine, thiadiazole, or triazole,        -   wherein the heterobicycle is other than chloro substituted            indole; and        -   the pyrazole, when substituted, is substituted with other            than trifluoromethyl,

or a pharmaceutically acceptable salt thereof.

The present invention provides compound having the structure:

-   -   wherein    -   R₁, R₂, R₃, R₄, and R₅ are each independently H, halogen, CF₃ or    -   C₁-C₄ alkyl;    -   R₆ is H, OH, or halogen;    -   B′ is a substituted or unsubstituted phenyl, pyridine,        pyrimidine, benzyl, pyrrolidine, sulfolane, oxetane, CO₂H or        (C₁-C₄ alkyl)-CO₂H,        -   wherein the substituted phenyl is substituted with other            than trifluoromethyl or 3-(methyl carboxylate), the            substituted pyridine is substituted with other than            trifluoromethyl and the substituted pyrrolidine is            substituted with other than hydroxamic acid, and the            substituted or unsubstituted pyrrolidine is bound to the            carbonyl through a carbon-carbon bond,

or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Structure of bisretinoid A2E, a cytotoxic component of retinallipofuscin.

FIG. 2. Structure of bisretinoid atRAL di-PE (all-transretinaldimer-phosphatidyl ethanolamine), a cytotoxic component of retinallipofuscin. R1 and R2 refer to various fatty acid constituents.

FIG. 3. Structure of bisretinoid A2-DHP-PE, a cytotoxic component ofretinal lipofuscin.

FIG. 4. Visual cycle and biosynthesis of A2E. A2E biosynthesis beginswhen a portion of all-trans-retinal escapes the visual cycle (yellowbox) and non-enzymatically reacts with phosphatidyl-ethanolamine formingthe A2E precursor, A2-PE. Uptake of serum retinol to the RPE (gray box)fuels the cycle.

FIG. 5. Three-dimensional structure of the RBP4-TTR-retinol complex.Tetrameric TTR is shown in blue, light blue, green and yellow (largeboxed region). RBP is shown in red (unboxed region) and retinol is shownin gray (small boxed region) (28).

FIG. 6. Structure of fenretinide, [N-(4-hydroxy-phenyl)retinamide,4HRP], a retinoid RBP4 antagonist.

FIG. 7. Schematic depiction of the HTRF-based assay format forcharacterization of RBP4 antagonists disrupting retinol-induced RBP4-TTRinteraction.

FIG. 8. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof Compounds 15-26. PPB: Plasma protein binding, H: Human, M: Mouse, R:Rat, D: Dog.

FIG. 9. RBP4 Binding. RBP4-TTR Interaction and/or Pharmacokinetic Dataof Compounds 27-38.

FIG. 10. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof Compounds 39-54.

FIG. 11. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof Compounds 55-67.

FIG. 12. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof Compounds 68-89.

FIG. 13. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof Compounds 90-109.

FIG. 14. RBP4 Binding, RBP4-TTR Interaction and/or Pharmacokinetic Dataof Compounds 110-129.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound having the structure:

-   -   wherein    -   R₁, R₂, R₃, R₄, and R₅ are each independently H, halogen, CF₃ or        C₁-C₄ alkyl;    -   R₆ is H, OH, or halogen;    -   B is a substituted or unsubstituted heterobicycle, pyridazine,        pyrazole, pyrazine, thiadiazole, or triazole,        -   wherein the heterobicycle is other than chloro substituted            indole; and        -   the pyrazole, when substituted, is substituted with other            than trifluoromethyl,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound wherein B is a substituted orunsubstituted heterobicycle.

In some embodiments, the compound wherein B has the structure:

wherein

α, β, χ, and δ are each independently absent or present, and whenpresent each is a bond;

X is C or N;

Z₁ is S, O, or N;

Z₂ is S, O, N or NR₇,

-   -   wherein R₇ is H, C₁-C₄ alkyl, or oxetane;

Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure.

In some embodiments of the above compound, the compound wherein B hasthe structure:

wherein

when α is present, then Z₁ and Z₂ are N, X is N, β is present, and χ andδ are absent, or when α is present, then Z₁ is O or S, Z₂ is N, X is C,χ is present, and β and δ are absent;

when α is absent, then Z₁ is N, Z₂ is N—R₇, X is C, β and δ are present,and χ is absent, or when α is absent, then Z₁ is N, Z₂ is O or S, X isC, β and δ are present, and χ is absent.

In some embodiments, the compound wherein B has the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and ϕ are each independently absent or present, and whenpresent each is a bond;

Z₁ is S, O or N;

Z₂ is S, O, N or N—R₇.

-   -   wherein R₇ is H, C₁-C₁₀ alkyl, or oxetane;

X is C or N;

Y₁, Y₂, Y₃, and each occurrence of Y₄ are each independently CR₈,C(R₉)₂, N—R₁₀, O, N, SO₂, or C═O.

-   -   wherein    -   R₈ is H, halogen, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₁₀        alkyl), C(O)OH, C(O)O(C₁-C₁₀ alkyl), C(O)—NH₂, C(O)—NH(C₁-C₄        alkyl), C(O)—NH(C₁-C₄ alkyl)₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—NH(C₁-C₁₀ alkyl), SO₃—N(C₁-C₁₀        alkyl)₂, CN, or CF;    -   R₉ is H or C₁-C₁₀ alkyl;    -   R₁₀ is H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, (C₁-C₁₀ alkyl)-CF₃,        (C₁-C₁₀ alkyl)-OCH₃, (C₁-C₁₀ alkyl)-halogen, SO₂—(C₁-C₁₀ alkyl),        SO₂—(C₁-C₁₀ alkyl)-CF₃, SO₂—(C₁-C₁₀ alkyl)-OCH₃, SO₂—(C₁-C₁₀        alkyl)-halogen, C(O)—(C₁-C₁₀ alkyl), C(O)—(C₁-C₁₀ alkyl)-CF₃,        C(O)—(C₁-C₁₀ alkyl)-OCH₃, C(O)—(C₁-C₁₀ alkyl)-halogen,        C(O)—NH—(C₁-C₁₀ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₁₀        alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments of the above compound the compound wherein B has thestructure:

wherein

when α is present, then Z₁ and Z₂ are N, X is N, β is present, and χ andδ are absent, or when α is present, then Z₁ is O or S, Z₂ is N, X is C,χ is present, and β and δ are absent;

when α is absent, then Z₁ is N, Z₂ is N—R₇, X is C, β and δ are present,and χ is absent, or when α is absent, then Z₁ is N, Z₂ is O or S, X isC, β and δ are present, and χ is absent.

when ε and ϕ are each present, then n=1, and each of Y₁, Y₂, Y₃, and Y₄are independently C—R₈ or N;

when ε and ϕ are each absent, then n=0, 1 or 2, each of Y₁, Y₂, Y₃, andeach occurrence of Y₄ are independently C(R₉)₂, N—R₁₀, O, or SO₂.

In some embodiments, the compound wherein

-   -   β and δ are present;    -   α, χ, ε, and ϕ are absent;    -   Z₁ is N;    -   Z₂ is O, S, or N—R₇,        -   wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and    -   X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 0;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁ and Y₃ are each CH₂ or C(CH₃)₂; and    -   Y₂ is O, SO₂, or N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₃—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH or oxetane.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁, Y₂ and Y₄ are each CH₂ or C(CH₃)₂; and    -   Y₃ is O, SO₂, or N—R₁₀.        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen SO₂—(C₁-C₄ alkyl),            SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃, SO₂—(C₁-C₄            alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl)-CF₃,            C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen,            C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄            alkyl)-C(O)OH, C(O)—NH₃ or oxetane.

In some embodiments, the compound wherein has the structure:

-   -   wherein    -   n is 1;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁, Y₃ and Y₄ are each CH₂ or C(CH₃)₂; and    -   Y_(a) is O, SO₂, or N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 2;    -   R₇ is H, C₂-C₄ alkyl, or oxetane;    -   Y₁, Y₃ and each occurrence of Y₄ are each CH₂ or C(CH₃)₂; and    -   Y₂ is O, SO₂, or N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₂,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)— (C₁-C₄            alkyl)-CF₃, C(O)— (C₁-C₄ alkyl)-OCH₂, C(O)— (C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₁₀ is H, CH₃, CH₂CH₃,CH₂CH₂CH₂, CH(CH₃)₂, CH₂CH(CH₃)₂, t-Bu, CH₂OCH₃, CH₂CF₂, CH₂Cl, CH₂F,CH₂CH₂OCH₃, CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is SO₃—CH₃, SO₂—CH₃CH₃,SO₂—CH₂—CH₂CH₃, SO₂—CH(CH₃)₂, SO₂—CH₃CH(CH₃)₂, SO₂-t-Bu, SO₂—CH₃OCH₃,SO₂—CH₂CF₂, SO₂—CH₂CH₂F, SO₂—CH₂CH₂OCH, SO₂—CH₂CH₂CF₃, SO₂—CH₂CH₂Cl,SO₂—CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is C(O)—CH₃, C(O)—CH₂C₃,C(O)—CH₂CH₂CH₃, C(O)—CH(CH₃)₂, C(O)—CH₂CH(CH₃)₂, C(O)-t-Bu,C(O)—CH₂OCH₃, C(O)—CH₂CF₃, C(O)—CH₂Cl, C(O)—CH₂F, C(O)—CH₂CH₂OCH₃,C(O)—CH₂CH₂CF₃, C(O)—CH₂CH₂Cl, C(O)—CH₂CH₂F,

In some embodiments, the compound wherein B has the structure:

In same embodiments, the compound wherein R₇ is H, CH₃, CH₂CH₃,CH(CH₃)₂, or

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   R₇ is H, C₁-C₄ alkyl, or oxetane;    -   Y₁ and Y₄ are each CH₂; and    -   Y₂ is C═O and Y₃ is N—R₁₀, or Y₃ is C═O and Y₂ is N—R₁₀,        -   wherein        -   R₁₀ is H or C₁-C₄ alkyl,

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₇ is H, CH₃, CH₂CH₃,CH(CH₃)₂, or

and each R₁₀ is H or CH₃.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   Y₁ and Y₄ are each CH₂; and    -   one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₃ is O, SO₂, or    -   N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   Y₁ and Y_(a) are each CH₂; and    -   one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₃ is O, SO₂, or        N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₂—(C₁-C₄ alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-OCH₃, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₃ or oxetane.

In some embodiments, the compound wherein B has the structure:

In same embodiments, the compound wherein R₁₀ is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, t-Bu. CH₂OCH₃, CH₂CF₂, CH₂Cl, CH₂F,CH₂CH₂OCH₃, CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is SO₂—CH₃, SO₂—CH₂CH₃,SO₂—CH₂CH₂CH₃, SO₂—CH(CH₃)₂, SO₂—CH₂CH(CH₂)₂, SO₂-t-Bu, SO₂—CH₂OCH₂,SO₂—CH₂CF₃, SO₂—CH₂Cl, SO₂—CH₂F, SO₂—CH₂CH₂OCH₂, SO₂—CH₂CH₂CF₂,SO₂—CH₂CH₂Cl, SO₂—CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is C(O)—CH₃, C(O)—CH₂CH₂,C(O)—CH₂CH₂CH₃, C(O)—CH(CH₃)₂, C(O)—CH₂CH(CH₃)₂, C(O)-t-Bu,C(O)—CH₂OCH₃, C(O)—CH₂CF₃, C(O)—CH₂Cl, C(O)—CH₂F, C(O)—CH₂CH₂OCH₂,C(O)—CH₂CH₂CF₃, C(O)—CH₂CH₂Cl, C(O)—CH₂CH₂F,

In some embodiments, the compound wherein

-   -   β, δ, ε, and ϕ are present;    -   α and χ are absent;    -   Z₁ is N;    -   Z₂ is O or N—R₇,        -   wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and    -   X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   R₇ is H, C₁-C₄ alkyl, or oxetane; and    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N,        -   wherein each R₈ is independently H, halogen, C₁-C₄ alkyl,            C₃-C₆ cycloalkyl, O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂,            C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN, or CF₃,

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₃ and Y₄ are each CH;    -   Y₁, Y₂, Y₃ are each CH and Y₄ is N;    -   Y₁, Y₂, Y₄ are each CH and Y₃ is N;    -   Y₁, Y₃, Y₄ are each CH and Y₂ is N; or    -   Y₂, Y₃, Y₄ are each CH and Y₁ is N.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₇ is H, CH₂CH₃, CH₃,CH(CH₃)₂, or

and each R₈ is independently H, Cl, Br, F, OCH₂, OCH₂CH₂, CF₂, CN, CH₃,CH₃CH₃, C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₂, or NHC(O)—N(CH₃)₂.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR_(a) or N,        -   wherein R₈ is H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            NHCH₃, NHC(O)—N(CH₃)₂, CN, or CF₃,

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₃ and Y₄ are each CH;    -   Y₁, Y₂, Y₃ are each CH and Y₄ is N;    -   Y₁, Y₂, Y₄ are each CH and Y₃ is N;    -   Y₁, Y₃, Y₄ are each CH and Y₂ is N; or    -   Y₂, Y₃, Y₄ are each CH and Y₁ is N.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   α and β are present;    -   χ, δ, ε, and ϕ are absent;    -   Z₁ is N;    -   Z₂ is N; and    -   X is N.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   Y₁ and Y₄ are each CH₂; and    -   one of Y₂ or Y₃ is CR₂ and the other of Y₂ or Y₃ is O, SO₂, or    -   N—R₁₀,        -   wherein        -   R₁₀ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, (C₁-C₄ alkyl)-CF₃,            (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄            alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃,            SO₃—(C₁-C₄ alkyl)-halogen, C(O)— (C₁-C₄ alkyl), C(O)— (C₁-C₄            alkyl)-CF₃, C(O)—(C₁-C₄ alkyl)-CH₂, C(O)—(C₁-C₄            alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl), C(O)—N(C₁-C₄ alkyl)₂,            (C₁-C₄ alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₁₀ is H, CH₃, CH₂CH₂,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH)₂, t-BU, CH₂OCH₃, CH₂CF₃, CH₂Cl, CH₂F,CH₂CH₂OCH₃, CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is SO_(h)—CH₂, SO₂—CH₃CH₁.SO₂—CH₂CH₂CH₃, SO₂—CH(CH₃)₂, SO₂—CH₂CH(CH₂)₂, SO₂-t-Bu, SO₂—CH₃OCH₁,SO₂O—CH₂CF₁, SO₂—CH₂Cl, SO₂—CH₂F, SO₂—CH₂CH₂OCH₃, SO₂—CH₂CH₃CF₃,SO₂—CH₂CH₂Cl, SO₂—CH₂CH₂F, or

In some embodiments, the compound wherein R₁₀ is C(O)—CH₃, C(O)—CH₂CH₃,C(O)—CH₂CH₂CH₂, C(O)—CH(CH₃)₂, C(O)—CH₂CH(CH₃)₂, C(O)-t-Bu,C(O)—CH₂OCH₁, C(O)— CH₂CF₃, C(O)—CH₂Cl, C(O)—CH₂F, C(O)CH₂CH₂OCH₃,C(O)—CH₂OCH₃, C(O)—CH₂CF₃, C(O)—CH₂Cl, C(O)—CH₂F, C(O)—CH₂CH₂OCH₃,C(O)—CH₂CH₂CF₃, C(O)—CH₂CH₂Cl, C(O)—CH₂CH₂F,

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   α, β, ε, and ϕ are present;    -   χ and δ are absent;    -   Z₁ is N;    -   Z₂ is N; and    -   X is N.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N,        -   wherein each Re is independently H, halogen, C₁-C₄ alkyl,            C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), CN, CF₃, C(O)OH, C(O)—NH₂,            C(O)—N(CH₃)₂, C(O)—NHCH₃, or NHC(O)—N(CH₃)₂

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein each Re is independently H,Cl, Br, F, OCH₃, OCH₂CH₃, CF₃, CN, CH₃, CH₃CH₃, C(O)OH, C(O)—NH₂,C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—NHCH₃, NHC(O)—N(CH₃)₂, SO₂—NHCH₃ orSO₂—N(CH₃)₂.

In some embodiments, the compound wherein

-   -   α, χ, ε, and ϕ are present;    -   β and δ are absent;    -   Z₁ is O or S;    -   Z₂ is N; and    -   X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N,        -   wherein each R₈ is independently H, halogen, O(C₂-C₄ alkyl),            C₃-C₆ cycloalkyl, CN, or CF₃.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, R₄, and R₅ are each H, t-Bu, Cl, F, or CF₃; and    -   R₆ is H, OH or F.

In some embodiments, the compound wherein R₁, R₂, R₃, and R₄ are each H,R₅ is CF₃; and R₆ is H.

In some embodiments, the compound having the structure:

In some embodiments, the compound having the structure:

In some embodiments, the compound having the structure:

In some embodiments, the compound having the structure:

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, and R₄ are each H and R₅ is CF₃, or    -   R₁ and R₂ are H, R₃ is F, R₄ is H and R₅ is CF₃, or    -   R₁, R₃ and R₅ are each H, and R₃ and R₄ are each CF₃, or    -   R₁, R₃ and R₄ are each H, R₂ is F, and R₅ is Cl, or    -   R₁, R₃ and R₄ are each H, R₂ is F, and R₅ is CF₃, or    -   R₁, R₂ and R₃ are each H, R₄ is F, and R₅ is Cl, or    -   R₁, R₂ and R₃ are each H, R₄ is F, and R₅ is CF₃; and    -   R₆ is H, OH or F.

In some embodiments, the compound having the structure:

In some embodiments, the compound wherein B has the structure:

wherein

α, β, χ, and δ are each independently absent or present, and whenpresent each is a bond;

X is C or N;

Z₃ is CH, S, O, N or NR₁₁,

-   -   wherein R₁₁ is H or C₁-C₁₀ alkyl;

Z₄ is CH, S, O, N or NR₁₂,

-   -   wherein R₁₂ is H or C₁-C₁₀ alkyl;

Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure.

In some embodiments of the above compound, the compound wherein

when α is present, then Z₃ are N, Z₄ is CH, X is N, β and δ are absent,

and χ is present;

when α is absent, then Z₃ is CH or N, Z₄ is NR₇, S, or O, X is C, β andδ are present, and χ is absent.

In some embodiments, the compound wherein B has the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and ϕ are each independently absent or present, and whenpresent each is a bond;

X is C or N;

Z₃ is CH, S, O, N or NR₁₁,

-   -   wherein R₁₁ is H or C₁-C₁₀ alkyl;

Z₄ is CH, S, O, N or NR₁₂,

-   -   wherein R₁₂ is H or C₁-C₁₀ alkyl;

Y₁, Y₂, Y₃, and each occurrence of Y₄ are each independently CR₁₃,C(R₁₄)₂, N—R₁₅, O, N, SO₂, or C═O,

-   -   wherein    -   R₁₃ is H, halogen, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₁₀        alkyl), C(O)OH, C(O)O(C₁-C₂₂ alkyl), C(O)—NH₂, C(O)—NH(C₁-C₄        alkyl), C(O)—NH(C₁-C₄ alkyl)₂, NHC(O)—NH(C₁-C₄ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—NH(C₁-C₁₀ alkyl), SO₂—N(C₁-C₁₀        alkyl)₂, CN, CF₃, imidazole, morpholino, or pyrrolidine    -   R₁₄ is H or C₁-C₁₀ alkyl;    -   R₁₅ is H, C₁-C₁₀ alkyl, C₁-C₆ cycloalkyl, (C₁-C₁₀ alkyl)-CF₃,        (C₁-C₁₀ alkyl)-OCH₃, (C₁-C₁₀ alkyl)-halogen, SO₂—(C₁-C₁₀ alkyl),        SO₂—(C₁-C₁₀ alkyl)-CF₃, SO₂—(C₁-C₁₀ alkyl)-OCH₃, SO₂—(C₁-C₁₀        alkyl)-halogen, C(O)—(C₁-C₁₀ alkyl), C(O)—(C₁-C₄ alkyl)-CF₃,        C(O)—(C₁-C₁₀ alkyl)-OCH₃, C(O)—(C₁-C₁a alkyl)-halogen,        C(O)—NH—(C₁-C₁₀ alkyl), C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄        alkyl)-C(O)OH, C(O)—NH₂ or oxetane.

In some embodiments of the above compound, the compound wherein wherein

when α is present, then Z₃ are N, Z₄ is CH, X is N, β and δ are absent,and χ is present;

when α is absent, then Z₃ is CH or N, Z₄ is NR₁₂, S, or O, X is C, β andδ are present, and χ is absent;

when δ and ϕ are each present, then n=1, and each of Y₁, Y₂, Y₃, and Y₄are independently C—R₁₃ or N;

when ε and ϕ are each absent, then n=0, 1 or 2, each of Y₁, Y₂, Y₃, andeach occurrence of Y₄ are independently C(R₁₄)₂, N—R₁₅, O, or SO₂.

In some embodiments of the above compound, the compound wherein

-   -   α, χ, ε, and ϕ are each present, β and δ are each absent, Z₃ is        CH, Z₄ is N; and X is N; or    -   χ, δ, ε, and ϕ are each present, α and β are each absent, Z₃ is        CH, Z₄ is N—R₁₂; and X is C; or    -   χ, δ, ε, and ϕ are each present, α β and are each absent, Z₃ is    -   N, Z₄ is N—R₁₂, S or O; and X is C.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1; and    -   Y₁, Y₂, Y₃, and Y₄ are each C—R₁₃ or N,        -   wherein R₁₃ is H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O) NHCH₃,            NHC(O)—N(CH₃)₂, CN, CF₃, imidazole, morpholino, or            pyrrolidine.

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₇, and Y₄ are each C—R₁₃; or    -   Y₁ is N, and Y₂, Y₃, and Y₄ are each C—R₁₃.

In some embodiments, the compound wherein B has the structure:

-   -   wherein is R₁₃ is H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,        O—(C₁-C₄ alkyl), C₁-C₄ cycloalkyl, C(O)OH, C(O)—NH₂,        C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, (CN, CF₃, imidazole,        morpholino, or pyrrolidine.

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1;    -   R₁₂ is H or C₁-C₄ alkyl;    -   Y₂, Y₃, and Y₄ are each C—R₁₃ or N,        -   wherein R₁₃ is H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,            NHC(O)—N(CH₃)₂, CN, CF₃, imidazole, morpholino, or            pyrrolidine.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein R₁₃ is H, CH₃, CF₃, OCH₃, F,Cl,

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   n is 1; and    -   Y₁, Y₂, Y₃, and Y₄ are each C—R₁₃ or N,        -   Wherein R₁₃ is H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,            O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,            NHC(O)—N(CH₃)₂, CN, CF₃, imidazole, morpholino, or            pyrrolidine.

In some embodiments, the compound wherein

-   -   Y₁, Y₂, Y₃, and Y₄ are each C—R₁₃, or    -   one of Y₁, Y₂, Y₃, or Y₄ is N and the other three of Y₁, Y₂, Y₃,    -   or Y₄ are each C—R₁₃,        -   wherein each R₁₃ is H.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₁₆, R₁₇, and N₁₆ are each H, halogen, C₁-C₄ alkyl or        C₃-C₆ cycloalkyl.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B is a substituted orunsubstituted pyridazine, pyrazole, pyrazine, thiadiazole, or triazole.

In some embodiments, the compound wherein B has the structure:

-   -   wherein R₁₉ is    -   H, halogen CN, CF₃, OH, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,        O(C₁-C₄ alkyl), C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄        alkyl)₂, C(O)OH, C(O)O(C₁-C₄ alkyl), C(O) (C₁-C₄ alkyl),        C(O)NH(SO₂)—(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₆ cycloalkyl),        C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₄ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₄ alkyl) or tetrazole.

In some embodiments, the compound wherein R₁₉ is H, Cl, Br, F, OCH₃,OCH₂CH₃, CF₃, CN, CH₃, CH₃CH₃, COOH, or COOCH₃.

In some embodiments, the compound wherein B has the structure:

In some embodiments, the compound wherein B has the structure:

-   -   wherein    -   R₂₀ is H, halogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O—(C₁-C₄        alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃,        NHC(O)—N(CH₃)₂, CN or CF₃.

In some embodiments, the compound wherein R₂₀ is H, Cl, Br, F, OCH₃,OCH₂CH₃, CF₃, CN, CH₃, or CH₃CH₃.

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, R₄, and R₅ are each H, Cl, F, t-Bu or CF₃; and    -   R₆ is H, OH or F.

In some embodiments, the compound wherein R₁, R₂, R₃, and R₄ are each H;R₅ is CF₃; and R₆ is H;

In some embodiments, the compound having the structure:

In some embodiments, the compound having the structure:

The present invention provides compound having the structure:

-   -   wherein    -   R₁, R₂, R₃, R₄, and R₅ are each independently H, halogen, CF₃ or        C₁-C₄ alkyl;    -   R₆ is H, OH, or halogen;    -   B. is a substituted or unsubstituted phenyl, pyridine,        pyrimidine, benzyl, pyrrolidine, sulfolane, oxetane, CO₂H or        alkyl)-CO₂H,        -   wherein the substituted phenyl is substituted with other            than trifluoromethyl or 3-(methyl carboxylate), the            substituted pyridine is substituted with other than            trifluoromethyl and the substituted pyrrolidine is            substituted with other than hydroxamic acid, and the            substituted or unsubstituted pyrrolidine is bound to the            carbonyl through a carbon-carbon bond,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H,        halogen CN, CF₃, OH, NH₂, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl,        O(C₁-C₄ alkyl), C(O)NH₂, C(O)NH(C₁-C₁₀ alkyl), C(O)N(C₁-C₄        alkyl)₂, C(O)OH, C(O)O(C₁-C₁₀ alkyl), C(O) (C₁-C₁₀ alkyl),        C(O)NH(SO₂)—(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl),        C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₁₀ alkyl) or tetrazole.

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₁, R₂₂, and R₂₃ are each independently H, halogen, OH,        NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,        C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄        alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl),        C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂,        or SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁, R₂₂, and R₂₃ are eachindependently F, Cl, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH, C(O)OCH₃

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₂, R₂₃, R₂₄ and R₂₅ are each independently H, halogen,        OH, CF₃, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl),        C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH,        C(O)O(C₁-C₄ alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄        alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₂, R₂₃, R₂₄ and R₂₅ are eachindependently H, F, Cl, CF₃, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH,C(O)OCH₃,

In some embodiments, the compound wherein R₂₂, R₂₄, R₂₅ are each H andR₂₃ is F, Cl, CH₃, CF₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH, C(O)OCH₃,

In some embodiments, the compound wherein B′ has the structure:

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H,        halogen CN, OH, NH₂, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₁₀        alkyl), C(O)NH₂, C(O)NH(C₁-C₁₀ alkyl), C(O)N(C₁-C₄ alkyl)₂,        C(O)OH, C(O)O(C₁-C₁₂ alkyl), C(O)(C₁-C₁₀ alkyl),        C(O)NH(SO₂)—(C₁-C₁₀ alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl),        C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₂₀ alkyl).

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₁ and R₂₅ are each independently H, halogen, OH, NH₂,        C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,        C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄        alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl),        C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁ and R₂₅ are eachindependently F, Cl, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH, C(O)OCH₃,

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₂, R₂₃, R₂₄ and R₂₅ are each independently H, halogen,        OH, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,        C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄        alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl),        C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁, R₂₂, R₂₃, R₂₄ and R₂₅ areeach independently H, F, Cl, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH,C(O)OCH₃,

In some embodiments, the compound wherein R₂₂, R₂₄, R₂₅ are each H andR₂₃ is F, Cl, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH, C(O)OCH₃,

In some embodiments, the compound wherein B′ has the structure:

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H,        halogen CN, CF₃, OH, NH₂, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl,        O(C₁-C₁₀ alkyl), C(O)NH₂, C(O)NH(C₁-C₁₀ alkyl), C(O)N(C₁-C₄        alkyl)₂, C(O)OH, C(O)O(C₁-C₁₀ alkyl), C(O)(C₁-C₁₀ alkyl),        C(O)NH(SO₂)—(C₁-C₁₀ alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl),        C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₁₀ alkyl),        NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₁₀ alkyl).

In some embodiments, the compound wherein B′ has the structure:

-   -   wherein R₂₁, R₂₂, R₂₄ and R₂₅ are each independently H, halogen,        OH, NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,        C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄        alkyl), C(O)(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl),        C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), or        O(SO₂)—NH₂, SO₂—(C₁-C₄ alkyl).

In some embodiments, the compound wherein R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H, F, Cl, CF₃, CH₃, OCH₃, OH, SO₂—CH₃, C(O)NH₂, C(O)OH,C(O)OCH₃,

In some embodiments, the compound wherein B′ has the structure

In some embodiments, the compound wherein B′ has the structure:

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, R₄, and R₅ are each H, Cl, F, t-Bu or CF₃; and    -   R₆ is H, OH or F.

In some embodiments, the compound wherein

-   -   R₁, R₂, R₃, and R₄ are each H,    -   R₅ is t-Bu or CF₃; and    -   R₆ is H.

In some embodiments, the compound having the structure:

The present invention provides a pharmaceutical composition comprising acompound of the present invention and a pharmaceutically acceptablecarrier.

The present invention provides a method for treating a diseasecharacterized by excessive lipofuscin accumulation in the retina in amammal afflicted therewith comprising administering to the mammal aneffective amount of a compound of the present invention or a compositionof the present invention

In some embodiments of the method, wherein the disease is furthercharacterized by bisretinoid-mediated macular degeneration.

In some embodiments of the method, wherein the amount of the compound iseffective to lower the serum concentration of RBP4 in the mammal.

In some embodiments of the method, wherein the amount of the compound iseffective to lower the retinal concentration of a bisretinoid inlipofuscin in the mammal.

In some embodiments of the method, wherein the bisretinoid is A2E. Insome embodiments of the method, wherein the bisretinoid is isoA2E. Insome embodiments of the method, wherein the bisretinoid is A2-DHP-PE. Insome embodiments of the method, wherein the bisretinoid is atRAL di-PE.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Age-Related MacularDegeneration.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is dry (atrophic)Age-Related Macular Degeneration.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Stargardt Disease.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Best disease.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is adult vitelliformmaculopathy.

In some embodiments of the method, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is Stargardt-likemacular dystrophy.

In some embodiments of the compound, B or B′ has the structure:

In some embodiments, bisretinoid-mediated macular degeneration isAge-Related Macular Degeneration or Stargardt Disease.

In some embodiments, the bisretinoid-mediated macular degeneration isAge-Related Macular Degeneration.

In some embodiments, the bisretinoid-mediated macular degeneration isdry (atrophic) Age-Related Macular Degeneration.

In some embodiments, the bisretinoid-mediated macular degeneration isStargardt Disease.

In some embodiments, the bisretinoid-mediated macular degeneration isBest disease.

In some embodiments, the bisretinoid-mediated macular degeneration isadult vitelliform maculopathy.

In some embodiments, the bisretinoid-mediated macular degeneration isStargardt-like macular dystrophy.

The bisretinoid-mediated macular degeneration may comprise theaccumulation of lipofuscin deposits in the retinal pigment epithelium.

As used herein, “bisretinoid lipofuscin” is lipofuscin containing acytotoxic bisretinoid. Cytotoxic bisretinoids include but are notnecessarily limited to A2E, isoA2E, atRAL di-PE, and A2-DHP-PE (FIGS. 1,2, and 3).

Except where otherwise specified, when the structure of a compound ofthis invention includes an asymmetric carbon atom, it is understood thatthe compound occurs as a racemate, racemic mixture, and isolated singleenantiomer. All such isomeric forms of these compounds are expresslyincluded in this invention, Except where otherwise specified, eachstereogenic carbon may be of the R or S configuration. It is to beunderstood accordingly that the isomers arising from such asymmetry(e.g., all enantiomers and diastereomers) are included within the scopeof this invention, unless indicated otherwise. Such isomers can beobtained in substantially pure form by classical separation techniquesand by stereochemically controlled synthesis, such as those described in“Enantiomers, Racemates and Resolutions” by J. Jacques, A. Collet and S.Wilen, Pub. John Wiley & Sons, N Y, 1981. For example, the resolutionmay be carried out by preparative chromatography on a chiral column.

The subject invention is also intended to include all isotopes of atomsoccurring on the compounds disclosed herein. Isotopes include thoseatoms having the same atomic number but different mass numbers. By wayof general example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

It will be noted that any notation of a carbon in structures throughoutthis application, when used without further notation, are intended torepresent all isotopes of carbon, such as ¹²C, ¹³C, or ¹⁴C. Furthermore,any compounds containing ¹³C or ¹⁴C may specifically have the structureof any of the compounds disclosed herein.

It will also be noted that any notation of a hydrogen in structuresthroughout this application, when used without further notation, areintended to represent all isotopes of hydrogen, such as ¹H, ²H, or ³H.Furthermore, any compounds containing ²H or ³H may specifically have thestructure of any of the compounds disclosed herein.

Isotopically-labeled compounds can generally be prepared by conventionaltechniques known to those skilled in the art using appropriateisotopically-labeled reagents in place of the non-labeled reagentsemployed.

The term “substitution”, “substituted” and “substituent” refers to afunctional group as described above in which one or more bonds to ahydrogen atom contained therein are replaced by a bond to non-hydrogenor non-carbon atoms, provided that normal valencies are maintained andthat the substitution results in a stable compound. Substituted groupsalso include groups in which one or more bonds to a carbon(s) orhydrogen(s) atom are replaced by one or more bonds, including double ortriple bonds, to a heteroatom. Examples of substituent groups includethe functional groups described above, and halogens (i.e., F, Cl, Br,and I); alkyl groups, such as methyl, ethyl, n-propyl, isoproplyl,n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, suchas methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such asphenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) andp-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy);heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl,methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto;sulfanyl groups, such as methylsulfanyl, ethylsulfanyl andpropylsulfanyl; cyano; amino groups, such as amino, methylamino,dimethylamino, ethylamino, and diethylamino; and carboxyl. Wheremultiple substituent moieties are disclosed or claimed, the substitutedcompound can be independently substituted by one or more of thedisclosed or claimed substituent moieties, singly or plurally. Byindependently substituted, it is meant that the (two or more)substituents can be the same or different.

In the compounds used in the method of the present invention, thesubstituents may be substituted or unsubstituted, unless specificallydefined otherwise.

In the compounds used in the method of the present invention, alkyl,heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groupscan be further substituted by replacing one or more hydrogen atoms withalternative non-hydrogen groups. These include, but are not limited to,halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

It is understood that substituents and substitution patterns on thecompounds used in the method of the present invention can be selected byone of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art from readily available starting materials. If asubstituent is itself substituted with more than one group, it isunderstood that these multiple groups may be on the same carbon or ondifferent carbons, so long as a stable structure results.

In choosing the compounds used in the method of the present invention,one of ordinary skill in the art will recognize that the varioussubstituents, i.e. R₁, R₂, etc. are to be chosen in conformity withwell-known principles of chemical structure connectivity.

As used herein, “alkyl” includes both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms and may be unsubstituted or substituted. Thus, C₁-C_(n) asin “C₁-C_(n) alkyl” is defined to include groups having 1, 2, . . . ,n−1 or n carbons in a linear or branched arrangement. For example,C₁-C₆, as in “C₁-C₆ alkyl” is defined to include groups having 1, 2, 3,4, 5, or 6 carbons in a linear or branched arrangement, and specificallyincludes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl,and hexyl. Unless otherwise specified contains one to ten carbons. Alkylgroups can be unsubstituted or substituted with one or moresubstituents, including but not limited to halogen, alkoxy, alkylthio,trifluoromethyl, difluoromethyl, methoxy, and hydroxyl.

As used herein, “C₁-C₄ alkyl” includes both branched and straight-chainC₁-C₄ alkyl.

As used herein, “alkenyl” refers to a non-aromatic hydrocarbon radical,straight or branched, containing at least 1 carbon to carbon doublebond, and up to the maximum possible number of non-aromaticcarbon-carbon double bonds may be present, and may be unsubstituted orsubstituted. For example, “C₂-C₆ alkenyl” means an alkenyl radicalhaving 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5carbon-carbon double bonds respectively. Alkenyl groups include ethenyl,propenyl, butenyl and cyclohexenyl.

As used herein, “heteroalkyl” includes both branched and straight-chainsaturated aliphatic hydrocarbon groups having at least 1 heteroatomwithin the chain or branch.

As used herein, “cycloalkyl” includes cyclic rings of alkanes of threeto eight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

As used herein, “heterocycloalkyl” is intended to mean a 5- to10-membered nonaromatic ring containing from 1 to 4 heteroatoms selectedfrom the group consisting of O, N and S, and includes bicyclic groups.“Heterocyclyl” therefore includes, but is not limited to the following:imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl,tetrahydrothiophenyl and the like. If the heterocycle contains nitrogen,it is understood that the corresponding N-oxides thereof are alsoencompassed by this definition.

As used herein, “aryl” is intended to mean any stable monocyclic,bicyclic or polycyclic carbon ring of up to 10 atoms in each ring,wherein at least one ring is aromatic, and may be unsubstituted orsubstituted. Examples of such aryl elements include but are not limitedto: phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl,indanyl, phenanthryl, anthryl or acenaphthyl. In cases where the arylsubstituent is bicyclic and one ring is non-aromatic, it is understoodthat attachment is via the aromatic ring.

The term “alkylaryl” refers to alkyl groups as described above whereinone or more bonds to hydrogen contained therein are replaced by a bondto an aryl group as described above. It is understood that an“alkylaryl” group is connected to a core molecule through a bond fromthe alkyl group and that the aryl group acts as a substituent on thealkyl group. Examples of arylalkyl moieties include, but are not limitedto, benzyl (phenylmethyl), p-trifluoromethylbenzyl(4-trifluoromethylphenylmethyl), 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl and the like.

The term “heteroaryl” as used herein, represents a stable monocyclic,bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein atleast one ring is aromatic and contains from 1 to 4 heteroatoms selectedfrom the group consisting of O, N and S. Bicyclic aromatic heteroarylgroups include but are not limited to phenyl, pyridine, pyrimidine orpyridazine rings that are (a) fused to a 6-membered aromatic(unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a5- or 6-membered aromatic (unsaturated) heterocyclic ring having twonitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated)heterocyclic ring having one nitrogen atom together with either oneoxygen or one sulfur atom; or (d) fused to a 5-membered aromatic(unsaturated) heterocyclic ring having one heteroatom selected from 0, Nor S. Heteroaryl groups within the scope of this definition include butare not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl,indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl,isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl,oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl,1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl,carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl,benzothiazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl,furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where theheteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively. Ifthe heteroaryl contains nitrogen atoms, it is understood that thecorresponding N-oxides thereof are also encompassed by this definition.

As used herein, “monocycle” includes any stable polycyclic carbon ringof up to 10 atoms and may be unsubstituted or substituted. Examples ofsuch non-aromatic monocycle elements include but are not limited to:cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of sucharomatic monocycle elements include but are not limited to: phenyl. Asused herein, “heteromonocycle” includes any monocycle containing atleast one heteroatom.

As used herein, “bicycle” includes any stable polycyclic carbon ring ofup to 10 atoms that is fused to a polycyclic carbon ring of up to 10atoms with each ring being independently unsubstituted or substituted.Examples of such non-aromatic bicycle elements include but are notlimited to: decahydronaphthalene. Examples of such aromatic bicycleelements include but are not limited to: naphthalene. As used herein,“heterobicycle” includes any bicycle containing at least one heteroatom.

The term “phenyl” is intended to mean an aromatic six membered ringcontaining six carbons, and any substituted derivative thereof.

The term “benzyl” is intended to mean a methylene attached directly to abenzene ring. A benzyl group is a methyl group wherein a hydrogen isreplaced with a phenyl group, and any substituted derivative thereof.

The term “pyridine” is intended to mean a heteroaryl having asix-membered ring containing 5 carbon atoms and 1 nitrogen atom, and anysubstituted derivative thereof.

The term “pyrimidine” is intended to mean a heteroaryl having asix-membered ring containing 4 carbon atoms and 2 nitrogen atoms whereinthe two nitrogen atoms are separated by one carbon atom, and anysubstituted derivative thereof.

The term “pyridazine” is intended to mean a heteroaryl having asix-membered ring containing 4 carbon atoms and 2 nitrogen atoms whereinthe two nitrogen atoms are adjacent to each other, and any substitutedderivative thereof.

The term “pyrazine” is intended to mean a heteroaryl having asix-membered ring containing 4 carbon atoms and 2 nitrogen atoms whereinthe two nitrogen atoms are separated by two carbon atoms, and anysubstituted derivative thereof.

The term “pyrrolidine” is intended to mean a non-aromatic five-memberedring containing four carbon atoms and one nitrogen atom, and anysubstituted derivative thereof.

The term “triazole” is intended to mean a heteroaryl having afive-membered ring containing two carbon atoms and three nitrogen atoms,and any substituted derivative thereof.

The term “imidazole” is intended to mean a heteroaryl having afive-membered ring containing three carbon atoms and two nitrogen atoms,and any substituted derivative thereof.

The term “thiadiazole” is intended to mean a heteroaryl having afive-membered ring containing two carbon atoms, two nitrogen atoms, andone sulfur atom and any substituted derivative thereof.

The term “pyrazole” is intended to mean a heteroaryl having afive-membered ring containing three carbon atoms and two nitrogen atomswherein the nitrogen atoms are adjacent to each other, and anysubstituted derivative thereof.

The term “triazine” is intended to mean a heteroaryl having asix-membered ring containing 3 carbon atoms and 3 nitrogen atoms, andany substituted derivative thereof.

The term “indole” is intended to mean a heteroaryl having afive-membered ring fused to a phenyl ring with the five-membered ringcontaining 1 nitrogen atom directly attached to the phenyl ring.

The term “benzimidazole” is intended to mean a heteroaryl having afive-membered ring fused to a phenyl ring with the five-membered ringcontaining 2 nitrogen atoms directly attached to the phenyl ring.

The term “oxatane” is intended to mean a non-aromatic four-membered ringcontaining three carbon atoms and one oxygen atom, and any substitutedderivative thereof.

The term “sulfolane” is intended to mean a non-aromatic five-memberedring containing four carbon atoms and one sulfur atom wherein the sulfuratom is doubly bonded to two oxygen atoms and any substituted derivativethereof.

The compounds used in the method of the present invention may beprepared by techniques well know in organic synthesis and familiar to apractitioner ordinarily skilled in the art. However, these may not bethe only means by which to synthesize or obtain the desired compounds.

The compounds of present invention may be prepared by techniquesdescribed in Vogel's Textbook of Practical Organic Chemistry, A. I.Vogel, A. R. Tatchell, B. S. Furnis, A. J. Hannaford, P. W. G. Smith,(Prentice Hall) 5^(th) Edition (1996), March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, JerryMarch, (Wiley-Interscience) 5^(th) Edition (2007), and referencestherein, which are incorporated by reference herein. However, these maynot be the only means by which to synthesize or obtain the desiredcompounds.

The compounds of present invention may be prepared by techniquesdescribed herein. The synthetic methods used to prepare Examples 1-103are used to prepare additional piperidine compounds which are describedin the embodiments herein.

The various R groups attached to the aromatic rings of the compoundsdisclosed herein may be added to the rings by standard procedures, forexample those set forth in Advanced Organic Chemistry: Part B: Reactionand Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed.Edition. (2007), the content of which is hereby incorporated byreference.

Another aspect of the invention comprises a compound of the presentinvention as a pharmaceutical composition.

As used herein, the term “pharmaceutically active agent” means anysubstance or compound suitable for administration to a subject andfurnishes biological activity or other direct effect in the treatment,cure, mitigation, diagnosis, or prevention of disease, or affects thestructure or any function of the subject. Pharmaceutically active agentsinclude, but are not limited to, substances and compounds described inthe Physicians' Desk Reference (PDR Network, LLC; 64th edition; Nov. 15,2009) and “Approved Drug Products with Therapeutic EquivalenceEvaluations” (U.S. Department Of Health And Human Services, 30thedition, 2010), which are hereby incorporated by reference.Pharmaceutically active agents which have pendant carboxylic acid groupsmay be modified in accordance with the present invention using standardesterification reactions and methods readily available and known tothose having ordinary skill in the art of chemical synthesis. Where apharmaceutically active agent does not possess a carboxylic acid group,the ordinarily skilled artisan will be able to design and incorporate acarboxylic acid group into the pharmaceutically active agent whereesterification may subsequently be carried out so long as themodification does not interfere with the pharmaceutically active agent'sbiological activity or effect.

The compounds of the present invention may be in a salt form. As usedherein, a “salt” is a salt of the instant compounds which has beenmodified by making acid or base salts of the compounds. In the case ofcompounds used to treat a disease, the salt is pharmaceuticallyacceptable. Examples of pharmaceutically acceptable salts include, butare not limited to, mineral or organic acid salts of basic residues suchas amines: alkali or organic salts of acidic residues such as phenols.The salts can be made using an organic or inorganic acid. Such acidsalts are chlorides, bromides, sulfates, nitrates, phosphates,sulfonates, formates, tartrates, maleates, malates, citrates, benzoates,salicylates, ascorbates, and the like. Phenolate salts are the alkalineearth metal salts, sodium, potassium or lithium. The term“pharmaceutically acceptable salt” in this respect, refers to therelatively non-toxic, inorganic and organic acid or base addition saltsof compounds of the present invention. These salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or by separately reacting a purified compound of theinvention in its free base or free acid form with a suitable organic orinorganic acid or base, and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19).

As salt or pharmaceutically acceptable salt is contemplated for allcompounds disclosed herein.

As used herein, “treating” means preventing, slowing, halting, orreversing the progression of a disease or infection. Treating may alsomean improving one or more symptoms of a disease or infection.

The compounds of the present invention may be administered in variousforms, including those detailed herein. The treatment with the compoundmay be a component of a combination therapy or an adjunct therapy, i.e.the subject or patient in need of the drug is treated or given anotherdrug for the disease in conjunction with one or more of the instantcompounds. This combination therapy can be sequential therapy where thepatient is treated first with one drug and then the other or the twodrugs are given simultaneously. These can be administered independentlyby the same route or by two or more different routes of administrationdepending on the dosage forms employed.

As used herein, a “pharmaceutically acceptable carrier” is apharmaceutically acceptable solvent, suspending agent or vehicle, fordelivering the instant compounds to the animal or human. The carrier maybe liquid or solid and is selected with the planned manner ofadministration in mind. Liposomes are also a pharmaceutically acceptablecarrier.

The dosage of the compounds administered in treatment will varydepending upon factors such as the pharmacodynamic characteristics of aspecific chemotherapeutic agent and its mode and route ofadministration; the age, sex, metabolic rate, absorptive efficiency,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment being administered; thefrequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds used in the method of the presentinvention may comprise a single compound or mixtures thereof withadditional agents. The compounds can be administered in oral dosageforms as tablets, capsules, pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. The compounds may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, or introduced directly, e.g. byinjection, topical application, or other methods, into or onto a site ofinfection, all using dosage forms well known to those of ordinary skillin the pharmaceutical arts.

The compounds used in the method of the present invention can beadministered in admixture with suitable pharmaceutical diluents,extenders, excipients, or carriers (collectively referred to herein as apharmaceutically acceptable carrier) suitably selected with respect tothe intended form of administration and as consistent with conventionalpharmaceutical practices. The unit will be in a form suitable for oral,rectal, topical, intravenous or direct injection or parenteraladministration. The compounds can be administered alone or mixed with apharmaceutically acceptable carrier. This carrier can be a solid orliquid, and the type of carrier is generally chosen based on the type ofadministration being used. The active agent can be co-administered inthe form of a tablet or capsule, liposome, as an agglomerated powder orin a liquid form. Examples of suitable solid carriers include lactose,sucrose, gelatin and agar. Capsule or tablets can be easily formulatedand can be made easy to swallow or chew; other solid forms includegranules, and bulk powders. Tablets may contain suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Examples of suitableliquid dosage forms include solutions or suspensions in water,pharmaceutically acceptable fats and oils, alcohols or other organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Such liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents. Oral dosage formsoptionally contain flavorants and coloring agents. Parenteral andintravenous forms may also include minerals and other materials to makethem compatible with the type of injection or delivery system chosen.

Techniques and compositions for making dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). All of the aforementioned publications are incorporatedby reference herein.

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and the like. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds used in the method of the present invention may also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamallar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines. The compounds maybe administered as components of tissue-targeted emulsions.

The compounds used in the method of the present invention may also becoupled to soluble polymers as targetable drug carriers or as a prodrug.Such polymers include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and crosslinked or amphipathicblock copolymers of hydrogels.

Gelatin capsules may contain the active ingredient compounds andpowdered carriers, such as lactose, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as immediate release products or as sustained releaseproducts to provide for continuous release of medication over a periodof hours. Compressed tablets can be sugar coated or film coated to maskany unpleasant taste and protect the tablet from the atmosphere, orenteric coated for selective disintegration in the gastrointestinaltract.

For oral administration in liquid dosage form, the oral drug componentsare combined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Examples ofsuitable liquid dosage forms include solutions or suspensions in water,pharmaceutically acceptable fats and oils, alcohols or other organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Such liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

The compounds used in the method of the present invention may also beadministered in intranasal form via use of suitable intranasal vehicles,or via transdermal routes, using those forms of transdermal skin patcheswell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill generally be continuous rather than intermittent throughout thedosage regimen.

Parenteral and intravenous forms may also include minerals and othermaterials to make them compatible with the type of injection or deliverysystem chosen.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

Experimental Details

Materials and Methods

TR-FRET Assay for Retinol-Induced RBP4-TTR Interaction

Binding of a desired RBP4 antagonist displaces retinol and induceshindrance for RBP4-TTR interaction resulting in the decreased FRETsignal (FIG. 7). Bacterially expressed MBP-RBP4 and untagged TTR wereused in this assay. For the use in the TR-FRET assay the maltose bindingprotein (MBP)-tagged human RBP4 fragment (amino acids 19-201) wasexpressed in the Gold(DE3)pLysS E. coli strain (Stratagene) using thepMAL-c4x vector. Following cell lysis, recombinant RBP4 was purifiedfrom the soluble fraction using the ACTA FPLC system (GE Healthcare)equipped with the 5-ml the MBP Trap HP column. Human untagged TTR waspurchased from Calbiochem. Untagged TTR was labeled directly with Eu³⁺Cryptate-NHS using the HTRF Cryptate Labeling kit from CisBio followingthe manufacturer's recommendations. HTRF assay was performed in whitelow volume 384 well plates (Greiner-Bio) in a final assay volume of 16μl per well. The reaction buffer contained 10 mM Tris-HCl pH 7.5, 1 mMDTT, 0.05% NP-40, 0.05% Prionex, 6% glycerol, and 400 mM KF. Eachreaction contained 60 nM MBP-RBP4 and 2 nM TTR-Eu along with 26.7 nM ofanti-MBP antibody conjugated with d2 (Cisbio). Titration of testcompounds in this assay was conducted in the presence of 1 μM retinal.All reactions were assembled in the dark under dim red light andincubated overnight at +4° C. wrapped in aluminum foil. TR-FRET signalwas measured in the SpectraMax M5e Multimode Plate Reader (MolecularDevice). Fluorescence was excited at 337 nm and two readings per wellwere taken: Reading 1 for time-gated energy transfer from Eu(K) to d2(337 nm excitation, 668 nm emission, counting delay 75 microseconds,counting window 100 microseconds) and Reading 2 for Eu(K) time-gatedfluorescence (337 nm excitation, 620 nm emission, counting delay 400microseconds, counting window 400 microseconds). The TR-FRET signal wasexpressed as the ratio of fluorescence intensity: Flu₆₆₅/Flu₆₂₀×10,000.

Scintillation Proximity RBP4 Binding Assay

Untagged human RBP4 purified from urine of tubular proteinuria patientswas purchased from Fitzgerald Industries International. It wasbiotinylated using the EZ-Link Sulfo-NHS-LC-Biotinylation kit fromPierce following the manufacturer's recommendations. Binding experimentswere performed in 96-well plates (OptiPlate, PerkinElmer) in a finalassay volume of 100 μl per well in SPA buffer (1×PBS, pH 7.4, 1 mM EDTA,0.1% BSA, 0.5% CHAPS). The reaction mix contained 10 nM ³H-Retinol (48.7Ci/mmol; PerkinElmer), 0.3 mg/well Streptavidin-PVT beads, 50 nMbiotinylated RBP4 and a test compound. Nonspecific binding wasdetermined in the presence of 20 μM of unlabeled retinol. The reactionmix was assembled in the dark under dim red light. The plates weresealed with clear tape (TopSeal-A: 96-well microplate, PerkinElmer),wrapped in the aluminum foil, and allowed to equilibrate 6 hours at roomtemperature followed by overnight incubation at +4° C. Radiocounts weremeasured using a TopCount NXT counter (Packard Instrument Company).

General Procedure (GP) for Preparing Intermediates for Synthesis ofPiperidine Compounds

Conditions: A1) carboxylic acid, HBTU, Et₃N, DMF; A2) carboxylic acid,EDCI, HOBt, i-Pr₂NEt, DMF; A3) acid chloride, Et₃N, CH₂Cl₂.

General Procedure (GP-A1) for Carboxamide Formation:

A mixture of amine I (1 equiv), desired carboxylic acid (1 equiv),triethylamine (Et₃N) (3 equiv), and2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) (1.5 equiv) in DMF (0.25 M) was stirred at room temperature untilthe reaction was complete by LC-MS. The mixture was diluted with H₂O andextracted with EtOAc. The combined organic extracts were washed withH₂O, brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by silica gelchromatography (typical eluents included either a mixture of or hexanesand EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired carboxamide II.The product structure was verified by ¹H NMR and by mass analysis.

General Procedure (GP-A2) for Carboxamide Formation:

A mixture of amine I (1 equiv), desired carboxylic acid (1 equiv),N,N-diisopropylethylamine (i-Pr₂NEt) (3 equiv),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.5 equiv) andhydroxybenzotriazole (HOBt) (1.5 equiv) in DMF (0.25 M) was stirred atroom temperature until the reaction was complete by LC-MS. The mixturewas diluted with H₂O and extracted with EtOAc. The combined organicextracts were washed with H₂O, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (typical eluents included either a mixtureof or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired carboxamide II.The product structure was verified by ¹H NMR and by mass analysis.

General Procedure (GP-A3) for Carboxamide Formation:

A mixture of amine I (1 equiv), Et₁N (3 equiv), and acid chloride (1equiv) in CH₂Cl₂ (0.25 M) was stirred at ambient temperature until thereaction was complete by LC-MS. The mixture was washed with H₂O, brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography (typicaleluents included either a mixture of or hexanes and EtOAc or a mixtureof CH₂Cl₂ and a 90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) toafford the desired carboxamides II. The product structure was verifiedby ¹H NMR and by mass analysis.

General Procedures for Preparing(4-Phenylpiperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanoneCarboxamides IV

Conditions: B) acid chloride, Et₃N, CH₂Cl₂.

General Procedure (GP-8) for Carboxamide Formation:

A Mixture of amine III (1 equiv), desired acid chloride (1 equiv) andtriethylamine (Et₃N) (3 equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C.to room temperature until the reaction was complete by LC-MS. Themixture was diluted with H₂O and extracted with CH₂Cl₂. The combinedorganic extracts were washed with H₂O, brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography (typical eluents includedeither a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredcarboxamides IV. The product structure was verified by ¹H NMR and bymass analysis.

General Procedures for Preparing(4-Phenylpiperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanoneSulfonamides V

Conditions: C) sulfonyl chloride, i-Pr₂NEt, CH₂Cl₂.

General Procedure (GP-C) for Sulfonamide Formation:

A mixture of amine III (1 equiv), desired sulfonyl chloride (1 equiv)and i-Pr₂NEt (3 equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C. to roomtemperature until the reaction was complete by LC-MS. The mixture wasdiluted with H₂O and extracted with CH₂Cl₂. The combined organicextracts were washed with H₂O, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (typical eluents included either a mixtureof or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired sulfonamides V.The product structure was verified by ¹H NMR and by mass analysis.

General Procedures for Preparing Alkylated(4-Phenylpiperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanonesVI

Conditions: D) aldehyde or ketone, NaBH(OAc)₃, CH₂Cl₂.

General Procedure (GP-D) for Sulfonamide Formation:

A mixture of amine III (1 equiv), desired aldehyde or ketone (1.5 equiv)and HOAc (6 equiv) in CH₂Cl₂ (0.25 M) was stirred for 16 hours at roomtemperature. To this was added sodium triacetoxyborohydride (NaBH(OAc)₃)and the mixture stirred at room temperature until the reaction wascomplete by LC-MS. The mixture was diluted with aqueous, saturatedNaHCO₃ solution and extracted with CH₂Cl₂. The combined organic extractswere washed with H₂O, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (typical eluents included either a mixtureof or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired amines VI. Theproduct structure was verified by ¹H NMR and by mass analysis.

General Procedure for Preparingtetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone Carboxamides VIII

Conditions: E) acid chloride, Et₃N, CH₂Cl₂.

General Procedure (GP-E) for Carboxamide Formation:

A mixture of amine VII (1 equiv), desired acid chloride (1 equiv) andtriethylamine (Et₃N) (3 equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C.to room temperature until the reaction was complete by LC-MS. Themixture was diluted with H₂O and extracted with CH₂Cl₂. The combinedorganic extracts were washed with H₂O, brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography (typical eluents includedeither a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredcarboxamides VIII. The product structure was verified by ¹H NMR and bymass analysis.

General Procedures for Preparing(4-Phenylpiperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanoneSulfonamide IX

Conditions: F) sulfonyl chloride, i-Pr₂NEt, CH₂Cl₂.

General Procedure (GP-F) for Sulfonamide Formation:

A mixture of amine VII (1 equiv), desired sulfonyl chloride (1 equiv)and i-Pr₂NEt (3 equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C. to roomtemperature until the reaction was complete by LC-MS. The mixture wasdiluted with H₂O and extracted with CH₂Cl₂. The combined organicextracts were washed with H₂O, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (typical eluents included either a mixtureof or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₂OH/concentrated NH₄OH) to afford the desired sulfonamides IX.The product structure was verified by ¹H NMR and by mass analysis.

General Procedures for Preparing Alkylated(4-Phenylpiperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanonesX

Conditions: G) aldehyde or ketone, NaBH(OAc)₃, CH₂Cl₂.

General Procedure (GP-G) for Sulfonamide Formation:

A mixture of amine VII (1 equiv), desired aldehyde or ketone (1.5 equiv)and HOAc (6 equiv) in CH₂Cl₂ (0.25 M) was stirred for 16 hours at roomtemperature. To this was added sodium triacetoxyborohydride (NaBH(OAc)₃)and the mixture stirred at room temperature until the reaction wascomplete by LC-MS. The mixture was diluted with aqueous, saturatedNaHCO₃ solution and extracted with CH₂Cl₂. The combined organic extractswere washed with H₂O, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (typical eluents included either a mixtureof or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired amines X. Theproduct structure was verified by ¹H NMR and by mass analysis.

General Procedures for Preparing(4-Phenylpiperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanoneCarboxamides XII

Conditions: H) acid chloride, Et₃N, CH₂Cl₂.

General Procedure (GP-H) for Carboxamide Formation:

A mixture of amine XI (1 equiv), desired acid chloride (1 equiv) andtriethylamine (Et₃N) (3 equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C.to room temperature until the reaction was complete by LC-MS. Themixture was diluted with H₂O and extracted with CH₂Cl₂. The combinedorganic extracts were washed with H₂O, brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography (typical eluents includedeither a mixture of or hexanes and EtOAc or a mixture of CH₂Cl₂ and a90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredcarboxamides XII, The product structure was verified by ¹H NMR and bymass analysis.

General Procedures for Preparing(4-Phenylpiperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanoneSulfonamides XIII

Conditions: I) sulfonyl chloride, i-Pr₂NEt, CH₂Cl₂.

General Procedure (GP-I) for sulfonamide formation:

A mixture of amine XI (1 equiv), desired sulfonyl chloride (1 equiv) andi-Pr₂NEt (3 equiv) in CH₂Cl₂ (0.25 M) was stirred from 0° C. to roomtemperature until the reaction was complete by LC-MS. The mixture wasdiluted with H₂O and extracted with CH₂Cl₂. The combined organicextracts were washed with H₂O, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (typical eluents included either a mixtureof or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired sulfonamidesXIII. The product structure was verified by ¹H NMR and by mass analysis.

General Procedures for Preparing Alkylated(4-Phenylpiperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanoneXIV

Conditions: J) aldehyde or ketone, NaBH(OAc)₃, CH₂Cl₂.

General Procedure (GP-J) for Sulfonamide Formation:

A mixture of amine XI (1 equiv), desired aldehyde or ketone (1.5 equiv)and HOAc (6 equiv) in CH₂Cl₂ (0.25 M) was stirred for 16 hours at roomtemperature. To this was added sodium triacetoxyborohydride (NaBH(OAc)₃)and the mixture stirred at room temperature until the reaction wascomplete by LC-MS. The mixture was diluted with aqueous, saturatedNaHCO₃ solution and extracted with CH₂Cl₂. The combined organic extractswere washed with H₂O, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (typical eluents included either a mixtureof or hexanes and EtOAc or a mixture of CH₂Cl₂ and a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired amines XIV. Theproduct structure was verified by ¹H NMR and by mass analysis.

Preparation 4-(2-(Trifluoromethyl)phenyl)piperidine Hydrochloride (5)

Step A: To a solution of 1-bromo-2-(trifluoromethyl)benzene (1, 35.0 g,156 mmol) in THF (350 mL) cooled to −78° C. under an atmosphere of N₂gas was slowly added a solution of n-BuLi (70.4 mL, 2.5 M in THF, 176mmol) over a period of 15 minutes. The mixture stirred at −78° C. for 40minutes, was allowed to warm to 0° C. and then cooled back down to −78°C. To this was added a solution of 1-benzylpiperidin-4-one (22.1 g, 117mmol) in THF (80 mL) over a period of 10 minutes. The resulting mixturecontinued to stir at −78° C. for 2 hours. The reaction was carefullyquenched with aqueous, saturated NH₄Cl solution (500 mL) and the mixturewas extracted with EtOAc (300 mL). The organic extract was washed withH₂O, brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resulting residue was chromatographed over silica gel(Isco CombiFlash Companion unit, 330 g Redisep column, 0-30% EtOAc inhexanes) to give 1-benzyl-4-(2-(trifluoromethyl)phenyl)piperidin-4-ol(2) as a light-yellow oil (29.2 g, 74%): ¹H NMR (500 MHz, CDCl₃) δ 7.78(d, J=1.6 Hz, 1H), 7.59 (m, 1H), 7.47 (m, 1H), 7.36 (m, 5H), 7.31 (m,2H), 3.58 (s, 2H), 2.80 (m, 2H), 2.55 (m, 28), 2.27 (m, 28), 1.88 (m,2H); MS (ESI+) m/z 336 [M+H]⁺.

Step B: A 0° C. cooled solution of 1-benzyl-4-(2-(trifluoromethyl)phenyl)piperidin-4-ol (2, 29.2 g, 87.1 mmol) in thionyl chloride (60 mL)stirred for 2 hours and was then diluted with CH₂Cl₂ (250 mL). Themixture was carefully poured into a solution of aqueous, saturatedNaHCO₃ solution (200 mL). The biphasic mixture was separated and theaqueous layer was further extracted with CH₂Cl₂ (400 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The resulting residue was chromatographed over silica gel(Isco CombiFlash Companion unit, 330 g Redisep column, 0-30% EtOAc inhexanes) to give1-benzyl-4-(2-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (3) asa light-yellow oil (13.5 g, 49%): ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d,J=1.6 Hz, 1H), 7.48 (m, 1H), 7.39 (m, 5H), 7.28 (m, 28), 5.56 (s, 1H),0.68 (s, 2H), 3.14 (m, 2H), 2.70 (m, 2H), 2.39 (m, 28); MS (ESI+) m/z318 [M+H]⁺.

Step C: A mixture of1-benzyl-4-(2-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (3,13.6 g, 42.5 mmol), 10% Pd/C (3.0 g), and ammonium formate (26.8 g, 425mmol) in CH₃OH (800 mL) was heated at reflux for 2 hours. The mixturecooled to ambient temperature and was filtered over Celite. The filtratewas concentrated and the resulting residue was chromatographed oversilica gel (Isco CombiFlash Companion unit, 330 g Redisep column, 0-10%CH₃OH with 1% NH₄OH in CH₂Cl₂) to give4-(2-(trifluoromethyl)phenyl)piperidine (4) as a colorless oil (2.0 g,21%): ¹H NMR (500 MHz, CDCl₃) δ 7.61 (d, J=1.7 Hz, 1H), 7.52 (m, 2H),7.29 (m, 1H), 3.21 (m, 2H), 3.07 (m, 1H), 2.80 (m, 2H), 2.33 (bs, 1H),1.77 (m, 4H); MS (ESI+) m/z 230 [M+H]⁺.

Step D: To a solution of 4-(2-(trifluoromethyl)phenyl)piperidine (4, 5.6g, 24.5 mmol) in CH₃CN (30 mL) was added a 4 M solution of HCl in1,4-dioxane (6.1 mL, 24.5 mmol) at ambient temperature. The mixturestirred for 10 minutes and was then concentrated under reduced pressureto give 4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride as a whitesolid (6.4 g, >99%): MS (ESI+) m/z 230 [M+H]⁺.

Preparation 4-(2-(Tert-butyl)phenyl)piperidine (8)

Step A: A mixture of 1-bromo-2-(tert-butyl)benzene (6, 445 mg, 2.09mmol), pyridin-4-ylboronic acid (514 mg, 4.18 mmol), Cs₂CO₃ (2.0 g, 6.27mmol), and Pd(PPh₃)₄ (121 mg, 0.105 mmol) in 1,4-dioxane (10 mL) and H₂O(3 mL) was heated at 100° C. for 16 hours. The mixture cooled to ambienttemperature and was extracted with EtOAc (100 mL). The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was chromatographed over silicagel (Isco CombiFlash Companion unit, 40 g Redisep column, 0-20% EtOAc inhexanes) to give 4-(2-(tert-butyl)phenyl)pyridine (7) as a white solid(428 mg, 97%): ¹H NMR (500 MHz, CDCl₃) δ 8.60 (m, 2H), 7.56 (d, J=1.6Hz, 1H), 7.37 (m, 1H), 7.26 (m, 3H), 6.90 (m, 1H), 1.20 (s, 9H); MS(ESI+) m/z 212 [M+H]⁺.

Step B: A mixture of 4-(2-(tert-butyl)phenyl)pyridine (7, 428 mg, 2.30mmol) and PtO₂ (70 mg) in CH₃OH (20 mL) and concentrated HCl (0.2 mL)was subjected to an atmosphere of Hz gas at a pressure of 50 PSI for 48hours. The mixture was diluted with CH₃OH and filtered over Celite andthe filtrate was concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂, washed with aqueous saturated NaHCO₃, dried overNa₂SO₄, filtered, and concentrated under reduced pressure.

The resulting residue was chromatographed over silica gel (IscoCombiFlash Companion unit, 12 g Redisep column, 0-5% CH₃OH with 1% NH₄₀Hin CH₂Cl₂) to 4-(2-(tert-butyl)phenyl)piperidine (8) as a white solid(60 mg, 13%): ¹H NMR (500 MHz, CDCl₃) δ 7.36 (m, 2H), 7.20 (m, 1H), 7.19(m, 1H), 3.35 (m, 3H), 2.77 (m 2H), 1.82 (m, 4H), 1.42 (s, 98); MS(ESI+) m/z 218 [M+H]⁺.

Preparation(4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(10)

Step A: To a solution of 4-(2-(trifluoromethyl)phenyl)piperidinehydrochloride (5, 0.228 g, 0.861 mmol),6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid (0.230 g, 0.861 mmol), and i-Pr₂NEt (0.49 mL, 2.81 mmol) in DMF (16mL) under an atmosphere of N₂ was added EDCI (0.215 g, 1.12 mmol) andHOBt (0.151 g, 1.12 mmol). The resulting solution was stirred at ambienttemperature for 18 hours. The reaction mixture was diluted with H₂O (80mL). The resulting precipitate was collected by filtration and washedwith H₂O (50 mL). Purification of the obtained solid by flash columnchromatography (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 6%CH₃OH in CH₂Cl₂ with 0.01% NH₄OH) gave tert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylateas a white film (9, 0.242 g, 58%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.97 (s,1H), 7.71-7.65 (m, 1H), 7.64-7.57 (m, 2H), 7.45-7.36 (m, 1H), 5.28-5.16(m, 1H), 4.74-4.61 (m, 1H), 4.51-4.36 (m, 2H), 3.66-3.50 (m, 2H),3.23-3.04 (m, 2H), 2.85-2.61 (m, 3H), 1.83-1.61 (m, 4H), 1.42 (s, 9H);ESI MS m/z 479 [M+H]⁺.

Step B: To a suspension of tert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(9, 0.240 g, 0.502 mmol) in CH₂Cl₂ (3 mL) was added a 2 N HCl solutionin Et₂O (3 mL) and the resulting solution was stirred at ambienttemperature for 18 hours. An additional 3 mL of a 2 N HCl solution inEt₂₀ was added followed by CH₃OH (3 mL). The resulting suspension wasstirred for 48 hours at ambient temperature. The mixture was dilutedwith Et₂O (30 mL) and the solids obtained by filtration. The solids werepartially dissolved in CH₂Cl₂ (150 mL) and washed with aqueous saturatedNaHCO₃ (50 mL). The aqueous layer was extracted with CH₂Cl₂ (3×50 mL)the combined organic extracts were concentrated under reduced pressureto provide(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas an off-white solid (10, 0.176 g, 928): ¹H NMR (500 MHz, DMSO-d₆) δ12.75 (br s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.65-7.60 (m, 2H), 7.43-7.38(m, 1H), 5.16-4.94 (m, 1H), 4.77-4.56 (m, 1H), 3.83-3.62 (m, 2H),3.18-3.05 (m, 2H), 2.95-2.66 (m, 3H), 2.59-2.52 (m, 2H), 2.36-2.15 (m,1H), 1.86-1.58 (m, 4H); ESI MS m/z 379 [M+H]⁺.

Preparation(4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(12)

Step A: To a solution of 4-(2-(trifluoromethyl)phenyl)piperidinehydrochloride (5, 0.230 g, 0.868 mmol),5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (0.235 g, 0.868 mmol), and i-Pr₂NEt (0.5 mL, 2.81 mmol) in DMF (16mL) under an atmosphere of 82 was added EDCI (0.215 g, 1.12 mmol) andHOBt (0.151 g, 1.12 mmol). The resulting solution was stirred at ambienttemperature for 18 hours. The reaction mixture was diluted with H₂O (80mL). The resulting precipitate was collected by filtration and washedwith H₂O (50 mL). Purification of the obtained solid by flash columnchromatography (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 6%CH₃OH in CH₂Cl₂ with 0.01% NH₄OH) gave tert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylateas a white film (11, 0.230 g, 52%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.00(s, 1H), 7.70-7.68 (m, 1H), 7.66-7.59 (m, 2H), 7.43-7.37 (m, 1H),5.30-5.18 (m, 1H), 4.77-4.64 (m, 1H), 4.53-4.39 (m, 2H), 3.69-3.49 (m,2H), 3.22-3.10 (m, 2H), 2.89-2.64 (m, 3H), 1.83-1.61 (m, 4H), 1.42 (s,9H); ESI MS m/z 479 [M+H]⁺.

Step B: To a solution of tert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(11, 0.600 g, 1.25 mmol) in CH₂Cl₂ (5 mL) was added trifluoroacetic acid(TFA) (2 mL). The mixture was concentrated under reduced pressure andfurther co-evaporated with CH₂Cl₂ (3×10 mL) and CH₃CN (3×10 mL). Theresulting residue was suspended in CH₃OH (50 mL) and 1N HCl (10 mL) wasthen added. The resulting solution was concentrated under reducedpressure and the residue obtained was again suspended in CH₃OH (50 mL)and 1N HCl (10 mL) was then added. The resulting solution wasconcentrated under reduced pressure and the solid obtained wastriturated with CH₃OH/CH₃CN to give(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (12, 0.332 g, 59%) mp=270-272°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 13.26 (s, 1H), 9.18 (s, 2H), 7.69 (d,J=7.9 Hz, 1H), 7.62 (s, 2H), 7.44-7.40 (m, 1H), 5.28 (d, J=12.3 Hz, 1H),4.68 (d, J=11.4 Hz, 1H), 4.24 (d, J=5.7 Hz, 2H), 3.38 (t, J=5.8 Hz, 2H),3.20-3.11 (m, 2H), 2.95 (t, J=5.8 Hz, 2H), 2.82 (t, J=12.4 Hz, 1H),1.85-1.63 (m, 4H); MS (APCI+) m/z 379 [M+H]⁺.

Preparation(1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(14)

Step A: A of mixture of5-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylicacid (0.286 g, 1.13 mmol), 4-(2-(trifluoromethyl)phenyl)piperidinehydrochloride (5, 0.300 g, 1.13 mmol),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (1.00 g, 2.26 mmol), and i-Pr₂NEt (0.438 g, 3.39mmol) in DMF (5 mL) stirred at ambient temperature for 16 hours and thenpoured into H₂O. The mixture was extracted with EtOAc (100 mL) and theorganic layer was washed with brine (2×100 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas chromatographed over silica gel (0-70% EtOAc in hexanes) to givetert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylateas a white solid (13, 0.560 g, 100%): ¹H NMR (300 MHz, CDCl₃) δ 7.80 (m,1H), 7.65 (d, J=7.7 Hz, 1H), 7.55-7.30 (m, 38), 4.79-3.89 (m, 6H),3.24-2.90 (m, 3H), 1.97-1.72 (m, 4H), 1.51 (s, 9H); MS (ESI+) m/z 465[M+H]⁺.

Step B: To a solution of tert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(0.560 g, 1.21 mmol) in CH₂Cl₂ (10 mL) was added a 2 N HCl solution inEt₂O (6 mL). The mixture was for 24 hours and was concentrated underreduced pressure. The residue was partitioned between CH₂Cl₂ andsaturated NaHCO₂. The aqueous layer was extracted with CH₂Cl₂ (3×30 mL)and the combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (14, 0.358 g, 81%), which was used as is in the nextstep.

Example 1: Preparation of(1-Methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of dihydro-2H-pyran-4(3H)-one (1.57 g, 15.7 mmol)in toluene (8 mL) was added lithium bis(trimethylsilyl)amide (1 M inTHF, 16.5 mL, 16.5 mmol) at 0° C. The mixture was stirred for 2 minutes.Ethyl 2-chloro-2-oxoacetate (1.06 g, 7.80 mmol) was then added and themixture was stirred at 0° C. for 5 minutes. A solution of HOAc (1.3 mL)in H₂O (12 mL) was added. The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas chromatographed over silica gel (0-40% EtOAc in hexanes) to give alight yellow oil. The material was dissolved in EtOH (10 mL).Methylhydrazine (0.115 mg, 2.50 mmol) was added. The solution was heatedat 75° C. for 1 h, cooled to ambient temperature and concentrated. Theresidue was chromatographed over silica gel (0-40% EtOAc in hexanes) togive ethyl1-methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate as awhite solid (0.264 g, 50%): ¹H NMR (300 MHz, CDCl₃) δ 4.82 (s, 2H), 4.37(q, J=7.1 Hz, 2H), 3.94 (m, 2H), 3.85 (s, 3H), 2.72 (m, 2H), 1.39 (t,J=7.1 Hz, 3H); MS (ESI+) m/z 211 [M+H]⁺.

Step B: To a solution of ethyl1-methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate (0.186 g,0.885 mmol) in CH₃OH (2 mL) and THF (2 mL) was added aqueous 2 N NaOH (2mL). The mixture was stirred for 2 hours and concentrated under reducedpressure. The residue was diluted with H₂O (25 mL), and acidified with 2N HCl to pH 5. The mixture was extracted with EtOAc (3×30 mL). Thecombined extracts were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to give a white solid (0.093 g, 57%). A mixtureof this material (0.031 g, 0.170 mmol),4-(2-(trifluoromethyl)phenyl)piperidine (5, 0.039 g, 0.170 mmol), EDCI(0.039 g, 0.204 mmol), HOBt (0.028 g, 0.204 mmol), Et₂N (0.072 mL, 0.510mmol) and CH₂Cl₂ (3 mL) was stirred at ambient temperature for 16 h andchromatographed over silica gel (0-4% CH₃OH in CH₂Cl₂ with 0.05% NH₄OH)to give(1-methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.060 g, 90%): mp 44-46° C.; ¹H NMR (300MHz, CDCl₃) δ 7.63 (d, J=7.8 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.42 (d,J=7.7 Hz, 1H), 7.30 (m, 1H), 5.36 (m, 1H), 4.88 (m, 3H), 3.95 (m, 2H),3.78 (s, 3H), 3.27-3.18 (m, 2H), 2.85-2.69 (m, 3H), 1.86-1.70 (m, 4H);MS (ESI+) m/z 394 [M+H]⁺.

Example 2: Preparation of(4-(2-(Trifluoromethyl)phenyl)piperidin-1-yl)(1,6,6-trimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methanone

Step A: To a solution of 2,2-dimethyldihydro-2H-pyran-4(3H)-one (1.00 g,7.80 mmol) in toluene (6 mL) was added lithium bis(trimethylsilyl)amide(1 M in THF, 8.19 mL, 8.19 mmol) at 0° C. The mixture was stirred for 2minutes followed by addition of ethyl 2-chloro-2-oxoacetate (1.06 g,7.80 mmol). The mixture was stirred at 0° C. for 5 minutes followed byaddition of HOAc (0.64 mL) in H₂O (8 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was chromatographed over silica gel (0-40% EtOAcin hexanes) to give a yellow oil. The material was dissolved in EtOH (10mL). Methylhydrazine (0.103 mg, 2.23 mmol) was added. The solution washeated at 75° C. for 1.5 h, cooled to ambient temperature andconcentrated. The residue was chromatographed over silica gel (0-40%EtOAc in hexanes) to give ethyl1,6,6-trimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate asa thick oil (0.135 g, 38%): ¹H NMR (300 MHz, CDCl₃) δ 4.80 (s, 2H), 4.32(q, J=7.1 Hz, 2H), 4.14 (s, 3H), 2.63 (s, 2H), 1.36 (t, J=7.1 Hz, 3H),1.30 (s, 6H); MS (ESI+) m/z 239 [M+H]⁺.

Step 8: To a solution of ethyl1,6,6-trimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate(0.118 g, 0.521 mmol) in CH₃OH (2 mL) and THF (2 mL) was added aqueous 2N NaOH (2 mL). The mixture stirred for 3 hours and was diluted with H₂Oand acidified to pH 5 with 2 N HCl. The mixture was extracted withCH₂Cl₂ and the organic extract was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give a white solid (0.085 g,71%). A mixture of this material, 4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.090 g, 0.338 mmol), EDCI (0.049 g,0.257 mmol), HOBt (0.035 g, 0.257 mmol), Et₃N (0.090 mL, 0.642 mmol) andCH₂Cl₂ (5 mL) was stirred at ambient temperature for 16 h andchromatographed over silica gel (0-4% CH₃OH in CH₂Cl₂) to give(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,6,6-trimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methanoneas a white solid (0.078 g, 86%): mp 58-64° C.; ¹H NMR (300 MHz, CDCl₃) δ7.65 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.38-7.31 (m, 2H), 4.67(s, 2H), 3.92 (s, 3H), 3.26-3.07 (m, 3H), 2.65 (s, 2H), 1.92-1.69 (m,6H), 1.31 (s, 6H); MS (ESI+) m/z 422 [M+H]⁺.

Example 3: Preparation of(1-methyl-5,5-dioxido-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of dihydro-2H-thiopyran-4(3H)-one (1.00 g, 8.61mmol) in toluene (4 mL) was added lithium bis(trimethylsilyl)amide (1 Min THF, 8.61 mL, 8.61 mmol) at 0° C. The mixture was stirred for 2minutes. Ethyl 2-chloro-2-oxoacetate (1.18 g, 8.61 mmol) was then addedand the mixture was stirred at 0° C. for 5 minutes followed by additionof a solution of HOAc (0.6 mL) in H₂O (30 mL). The resulting mixture wasextracted with EtOAc (20 mL) and the organic extract was washed withbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was chromatographed over silica gel (0-40%EtOAc in hexanes) to give a yellow oil. The material was dissolved inEtOH (20 mL). Methylhydrazine (0.202 mg, 4.39 mmol) was added. Thesolution was heated at 75° C. for 3 hours then cooled to ambienttemperature and concentrated under reduced pressure. The residue waschromatographed over silica gel (0-30% EtOAc in hexanes) to give ethyl1-methyl-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole-3-carboxylate as athick oil (0.093 g, 5%): ¹H NMR (300 MHz, CDCl₃) δ 4.36 (q, J=7.2 Hz,2H), 4.11 (s, 3H), 3.87 (s, 2H), 2.98-2.86 (m, 4H), 1.39 (t, J=7.1 Hz,3H); MS (ESI+) m/z 227 [M+H]⁺.

Step B: To a solution of ethyl1-methyl-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole-3-carboxylate(0.118 g, 0.521 mmol) in CH₃OH (2 mL) and THF (2 mL) was added aqueous 2N NaOH (2 mL). The mixture stirred for 1 hour then concentrated underreduced pressure. The residue was diluted with H₂O (5 mL), and acidifiedto pH 5 with 1 N HCl. A precipitate formed and was collected byfiltration and dried in vacuo (0.073 g, 71%). A mixture of thismaterial, 4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5,0.090 g, 0.338 mmol), EDCI (0.078 g, 0.406 mmol), HOBt (0.055 g, 0.406mmol), Et₃N (0.142 mL, 1.01 mmol) and CH₂Cl₂ (5 mL) was stirred atambient temperature for 16 hours and chromatographed over silica gel(0-4% CH₃OH in CH₂Cl₂) to give(1-methyl-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a thick oil (0.102 g, 74%): ¹H NMR(300 MHz, CDCl₃) δ 7.65 (d, J=7.8 Hz, 1H), 7.54 (m, 1H), 7.40-7.29 (m,2H), 4.86 (m, 1H), 3.91-2.91 (m, 13H), 1.96-1.49 (m, 4H); MS (ESI+) m/z410 [M+H]⁺.

Step C: To a solution of(1-methyl-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (0.102 g, 0.249 mmol) in CH₃CM (15 mL)and H₂O (8 mL) was added Oxone (0.612 g, 0.996 mmol). The mixture wasstirred for 3 hours, poured into saturated NaHCO₃ and extracted withEtOAc. The organic extract was washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waschromatographed over silica gel (0-4% CH₃OH in CH₂Cl₂) to give(1-methyl-5,5-dioxido-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.103 g, 93%): mp232-234° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J=7.8 Hz, 1H), 7.55 (brs, 1H), 7.34 (m, 2H), 4.84 (br s, H), 4.15-3.84 (m, 6H), 3.35-2.98 (m,7H), 2.00-1.54 (m, 4H); MS (ESI+) m/z 442 [M+H]⁺.

Example 4: Preparation of(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A solution of 5-fluoro-2-hydrazinylpyridine (0.460 g, 3.62 mmol)and ethyl 2-oxoacetate (50% in toluene, 0.739 g, 3.62 mmol) in CH₃OH (20mL) was heated at 60° C. for 1 hour, cooled to ambient temperature andconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂(20 mL). PhI(OAc)₂ (1.28 g, 3.98 mmol) was added and the mixture wasstirred for 1 hour and concentrated under reduced pressure. The residuewas chromatographed over silica gel (0-80% EtOAc in hexanes) to giveethyl 6-fluoro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate as anoff-white solid (0.331 g, 43%): ¹H NMR (300 MHz, CDCl₃) δ 9.18 (m, 1H),8.00-7.95 (m, 1H), 7.49-7.42 (m, 1H), 4.60 (q, J=7.1 Hz, 2H), 1.52 (t,J=7.1 Hz, 3H); MS (ESI+) m/z 210 [M+H]⁺.

Step B: To a solution of ethyl6-fluoro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.100 g, 0.478mmol) in THF (5 mL) was added a solution of LiOH hydrate (0.040 g, 0.956mmol) in H₂O (2 mL). The mixture stirred for 20 minutes and was thenacidified to pH 6 with 2 N HCl followed by subsequent concentrationunder reduced pressure. The resulting residue was added to a mixture of4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.127 g, 0.478mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.423 g, 0.956 mmol), i-Pr₂NEt (0.185 g, 1.43 mmol)in DMF (4 mL). The mixture stirred at ambient temperature for 16 hoursand was then poured into H₂O and extracted with EtOAc (30 mL). Theorganic layer was washed with brine (2×30 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas chromatographed over silica gel (0-50% EtOAc in hexanes) and freezedried to give(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.101 g, 53%): mp 168-170° C.; ¹H NMR (300 MHz, CDCl₃)δ 9.18 (s, 1H), 7.88 (m, 1H), 7.66 (d, J 7.5 Hz, 1H), 7.55-7.30 (m, 4H),5.76 (m, 1H), 4.99 (m, 1H), 3.40-3.30 (m, 2H), 2.98 (m, 1H), 2.03-1.76(m, 4H); MS (ESI+) m/z 393 [M+H]⁺.

Example 5: Preparation of(6-Methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A solution of 2-hydrazinyl-5-methoxypyridine (0.674 g, 4.84mmol) and ethyl 2-oxoacetate (50% in toluene, 0.988 g, 4.84 mmol) inCH₃OH (25 mL) was heated at 60° C. for 1 hour, then cooled to ambienttemperature and concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂ (25 mL) and PhI(OAc)₂ (1.71 g, 5.32 mmol) was added.The resulting mixture stirred for 16 hours then concentrated underreduced pressure. The residue was chromatographed over silica gel (0-80%EtOAc in hexanes) to give ethyl6-methoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate as an off-whitesolid (0.937 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 8.69 (dd, J=2.2, 0.6 Hz,1H), 7.84 (dd, J=9.8, 0.7 Hz, 1H), 7.27 (dd, J=9.8, 2.3 Hz, 1H), 4.58(q, J=7.1 Hz, 2H), 3.92 (s, 3H), 1.52 (t, J=7.1 Hz, 3H); MS (ESI+) m/z222 [M+H]⁺.

Step B: To a solution of ethyl6-methoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.060 g, 0.271mmol) in THF (5 mL) was added a solution of LiOH hydrate (0.034 g, 0.813mmol) in H₂O (3 mL). The mixture was stirred for 1 hour, was acidifiedto pH 6 with 2 N HCl, followed by concentration under reduced pressure.The residue was added to a mixture of4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.072 g, 0.271mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.240 g, 0.542 mmol), and i-Pr₂NEt (0.105 g, 0.813mmol) in DMF (5 mL). The mixture was stirred at ambient temperature for16 hours and then poured into H₂O. The mixture was extracted with EtOAc(30 mL) and the organic layer was washed with brine (2×30 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting residue was chromatographed over silica gel (0-50% EtOAc inhexanes) and freeze dried to give(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.094 g, 85%): mp 152-154° C.; ¹H NMR (300 MHz, CDCl₂)δ 8.70 (d, J=1.8 Hz, 1H), 7.76 (dd, J=9.9, 1.0 Hz, 1H), 7.65 (d, J=7.8Hz, 1H), 7.55-7.44 (m, 2H), 7.32 (t, J=7.8 Hz, 1H), 7.22 (dd, J=9.9, 2.4Hz, 1H), 5.76 (m, 1H), 4.97 (m, 1H), 3.90 (s, 3H), 3.39-3.29 (m, 2H),2.98 (m, 1H), 2.03-1.77 (m, 4H); MS (ESI+) m/z 405 [M+H]⁺.

Example 6: Preparation of(6,8-Dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of morpholin-3-one (0.442 g, 4.37 mmol) in CH₂Cl₂(10 mL) was added trimethyloxonium tetrafluoroborate (0.711 g, 4.81mmol). The mixture was stirred at ambient temperature for 3 hours andwas concentrated under reduced pressure. The residue was added to asolution of ethyl 2-hydrazinyl-2-oxoacetate (0.577 g, 4.37 mmol) inCH₃OH (25 mL) and the resulting mixture was heated at 60° C. for 16hours. The mixture cooled to ambient temperature and was concentratedunder reduced pressure. The residue was partitioned between aqueoussaturated NH₄Cl and CH₂Cl₂. The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0-100% EtOAc in hexaneswith 0.05% NH₄OH) to give ethyl6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-carboxylate as awhite solid (0.200 g, 23%): ¹H NMR (300 MHz, CDCl₃) δ 5.04 (s, 2H), 4.49(q, J 7.1 Hz, 2H), 4.41 (m, 2H), 4.06 (m, 2H), 1.46 (t, J=7.1 Hz, 3H);MS (ESI+) m/z 198 [14+H]⁺.

Step H: To a solution of ethyl6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine-3-carboxylate (0.072g, 0.365 mmol) in THF (3 mL) was added a solution of LiOH monohydrate(0.031 g, 0.730 mmol) in H₂O (2 mL). The mixture stirred for 20 minutesand was then acidified to pH 6 with 2 N HCl, and concentrated underreduced pressure. The resulting residue was added to a mixture of4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.097 g, 0.365mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.323 g, 0.730 mmol), and i-Pr₂NEt (0.142 g, 1.10mmol) in DMF (4 mL). The mixture stirred at ambient temperature for 16hours and was then poured into H₂O and subsequently extracted with EtOAc(30 mL). The organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed by reverse phase column (10-50% CH₃CN inH₂O) and freeze dried to give(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone as an off-white solid (0.062 g, 44%): mp202-203° C.; NMR (300 MHz, CDCl₃) δ 7.61 (d, J=7.8 Hz, 1H), 7.51 (m,2H), 7.31-7.25 (m, 1H), 5.03 (s, 2H), 4.54-4.47 (m, 2H), 4.38-4.27 (m,2H), 4.08-4.00 (m, 2H), 3.91-3.74 (m, 2H), 3.62-3.50 (m, 1H), 3.01-2.80(m, 2H), 2.44-2.32 (m, 2H), 1.69-1.56 (m, 4H); MS (ESI+) m/z 407 (M+H);HPLC>99% purity (method C). ¹H NMR (300 MHz, CDCl₃) δ 7.65 (d, J=7.8 Hz,1H), 7.52 (t, J=7.5 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.32 (t, J=7.8 Hz,1H), 5.44-5.39 (m, 1H), 5.09-4.98 (m, 2H), 4.90-4.84 (m, 1H), 4.53-4.44(m, 1H), 4.36-4.28 (m, 1H), 4.11-3.98 (m, 2H), 3.30-3.21 (m, 2H),2.94-2.85 (m, 1H), 2.031.71 (m, 4H); MS (ESI+) m/z 381 [M+H]⁺.

Example 7: Preparation of 1-(3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)ethanone

Step A: Following general procedure GP-H,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (14) and acetyl chloride were converted to1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)ethanone as a white solid (0.043 g, 48%):mp 186-192° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J=7.8 Hz, 1H), 7.54(t, J=7.5 Hz, 1H), 7.42-7.31 (m, 2H), 4.91-4.55 (m, 5H), 4.21 (m, 1H),3.41-2.92 (m, 3H), 2.17 (d, J 4.5 Hz, 3H), 1.98-1.76 (m, 4H); MS (ESI+)m/z 407 [M+H]⁺.

Example 8: Preparation of(5-(Methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-I,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl) piperidin-1-yl)methanone (14) and methanesulfonyl chloride wereconverted to(5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.053 g, 54%): ¹H NMR (300 MHz, CDCl₃) δ7.66 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.41-7.32 (m, 2H),4.82-4.09 (m, 6H), 3.30-2.22 (m, 2H), 3.93 (m, 4H), 2.05-1.74 (m, 4H);MS (ESI+) m/z 443 [M+H]⁺.

Example 9: Preparation of(5-Methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-J,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (14) and formaldehyde were converted to(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.060 g, 57%): ¹H NMR (300 MHz, CDCl₃) δ 7.65 (d,J=7.8 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.42-7.30 (m, 2H), 4.85 (m, 1H),4.32 (m, 1H), 3.83 (s, 4H), 3.28-2.88 (m, 3H), 2.63 (s, 3H), 2.01-1.77(m, 4H); MS (ESI+) m/z 379 [M+H]⁺.

Example 10: Preparation of(5-Methyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of tert-butyl 4-oxoazepane-1-carboxylate (0.300 g,1.41 mmol) in THF (10 mL) was added bis(trimethylsilyl)amide (1 M THF,1.55 mL, 1.55 mmol) over 10 min at −78° C., and the mixture stirred for1 hour at this temperature. Diethyl oxalate (0.206 g, 1.41 mmol) wasthen added and the mixture stirred for an additional 2 hours at −78° C.The mixture was allowed to warm to ambient temperature, and was quenchedwith saturated aqueous NH₄Cl. The resulting mixture was extracted withEtOAc and the extract was washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas chromatographed over silica gel (0-40% EtOAc in hexanes) to givetert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxoazepane-1-carboxylate as an oil(0.144 g, 32%): ¹H NMR (300 MHz, CDCl₃) δ 15.66 (s, 1H), 4.45-4.32 (m,4H), 3.61 (m, 2H), 2.80 (m, 2H), 1.88-1.80 (m, 2H), 1.45-1.37 (m, 12H);MS (ESI+) m/z 214 [M-CO₂C₄H₈+H].

Step B: To a solution of tert-butyl3-(2-ethoxy-2-oxoacetyl)-4-oxoazepane-1-carboxylate (0.144 g, 0.460mmol) in THF (3 mL) was added a solution of hydrazine in THF (1 M, 2.3mL). The reaction mixture was stirred at ambient temperature for 2 hoursand concentrated under reduced pressure. The residue was chromatographedover silica gel (0-10% CH₃OH in CH₂Cl₂) to give 5-tert-butyl 3-ethyl4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-3,5(1H)-dicarboxylate as athick oil (0.100 g, 70%): MS (ESI+) m/z 254 [M-C₄H₈+H].

Step C: To a solution of 5-tert-butyl 3-ethyl4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-3,5(1H)-dicarboxylate (0.100 g,0.323 mmol) in THF (3 mL) and CH₃OH (0.5 mL) was added a solution ofLiOH monohydrate (0.067 g, 1.62 mmol) in H₂O (2 mL). The mixture wasstirred at ambient temperature for 16 hours, acidified to pH 6 with 2 NHCl. The mixture was concentrated under reduced pressure and theresulting residue was added to a mixture of added4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.086 g, 0.323mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.286 g, 0.969 mmol), and i-Pr₂NEt (0.17 mL, 0.969mmol) in DMF (3 mL). The mixture stirred at ambient temperature for 8hours and was diluted with H₂O and extracted with EtOAc (30 mL). Theextract was washed with brine (2×30 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The resulting residue waschromatographed over silica gel (0-100% EtOAc in hexanes) to givetert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylateas a thick oil (0.054 g, 34%): MS (ESI+) m/z 493 [M+H]⁺.

Step D: To a solution of tert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate(0.054 g, 0.110 mmol) in CH₃OH (10 mL) was added a 2 N solution of HClin Et₂O (5 mL). The reaction was stirred for 6 hours and wasconcentrated under reduced pressure. The material was dissolved in CH₂OH(3 mL) and aqueous formaldehyde (37% solution in H₂O, 0.011 mL, 0.132mmol) was added, followed by NaBH(OAc)₃ (0.047 g, 0.22 mmol). Themixture was stirred for 30 minutes, and was subsequently poured intosaturated NaHCO₃ and extracted with EtOAc (3×30 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas chromatographed by reverse phase chromatography (0-50% CH₃CN in H₂O)and freeze dried to give(5-methyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.034 g, 76%):%): mp 75-85° C.; ¹H NMR (300 MHz,CDCl₂) δ 7.63 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.42 (d, J=7.7Hz, 1H), 4.84-4.51 (m, 2H), 3.73 (s, 2H), 3.25-2.80 (m, 7H), 2.42 (s,3H), 1.90-1.74 (m, 7H); MS (ESI+) m/z 407 [M+H]⁺.

Example 11: Preparation of(6-Methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a mixture of sodium6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.250 g, 0.947mmol) and CH₃OH (5 mL) was added aqueous HCl (3 N, 0.32 mL). The mixturewas stirred for 5 minutes and was concentrated under reduced pressure.The residue was added to a mixture of4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.252 g, 0.947mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.838 g, 1.89 mmol), and i-Pr₂NEt (0.49 mL, 2.84mmol) in DMF (5 mL). The mixture stirred for 16 hours then poured intoH₂O. The aqueous mixture was extracted with EtOAc (80 mL) and theorganic layer was washed with brine (2×80 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas chromatographed over silica gel (0-50% EtOAc in hexanes) to give(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a light yellow solid (0.240 g, 56%): ¹H NMR(300 MHz, CDCl₃) δ 9.38 (m, 1H), 7.78 (m, 1H), 7.66 (d, J=7.8 Hz, 1H),7.55-7.43 (m, 3H), 7.32 (d, J=7.7 Hz, 1H), 5.73-5.68 (m, 1H), 5.00-4.95(m, 1H), 3.40-3.28 (m, 2H), 3.03-2.94 (m, 1H), 2.01-1.81 (m, 4H); MS(ESI+) m/z 455 [M+H+2].

Step B: To a mixture of(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.064 g, 0.141 mmol), Fe(acac)₃ (0.005 g, 0.0141 mmol), NMP (0.05mmol), and THF (1 mL) was added CH₃MgBr (1.4 M solution in THF/toluene,0.15 mL, 0.212 mmol) dropwise at 0° C. The resulting mixture was warmedto ambient temperature and stirred for 1 hour. Additional CH₃MgBrsolution (1.4 M solution in THF/toluene, 0.15 mL, 0.212 mmol) was addedand the mixture was stirred for an additional 1 hour. 2 N HCl (0.5 mL)was then added and the mixture was poured into saturated NaHCO₃ andextracted with EtOAc. The extract was washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0-70% EtOAc in hexanes) andfreeze dried to give(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.044 g, 80%): mp 145-147°C.; ¹H NMR (300 MHz, CDCl₃) δ 8.92 (m, 1H), 7.78 (m, 1H), 7.66 (d, J=7.8Hz, 1H), 7.55-7.44 (m, 2H), 7.34-7.26 (m, 2H), 5.70-5.65 (m, 1H), 4.98(m, 1H), 3.38-3.28 (m, 2H), 3.02-2.92 (m, 1H), 2.39 (s, 3H), 2.07-1.67(m, 4H); MS (ESI+) m/z 389 [M+H]⁺.

Example 12: Preparation of(6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A solution of 5-chloro-2-hydrazinylpyridine (1.19 g, 8.29 mmol)and ethyl 2-oxoacetate (50% in toluene, 1.70 g, 8.29 mmol) in CH₃OH (30mL) was heated at 60° C. for 1 hour, cooled to ambient temperature andconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂(30 mL) and PhI(OAc)₂ (2.67 g, 8.29 mmol) was added. The resultingmixture stirred for 2 hours and was concentrated under reduced pressure.The resulting residue was chromatographed over silica gel (0-50% EtOAcin hexanes) to give ethyl6-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate as an yellow solid(1.61 g, 86%): ¹H NMR (300 MHz, CDCl₃) δ 9.26 (m, 1H), 7.93 (dd, J=9.7,0.9 Hz, 1H), 7.47 (dd, J=9.7, 1.9 Hz, 1H), 4.60 (q, J=7.1 Hz, 2H), 1.52(t, J=7.1 Hz, 3H).

Step B: To a solution of ethyl6-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.058 g, 0.257mmol) in THF (4 mL) was added a solution of LiOH monohydrate (0.032 g,0.771 mmol) in H₂O (2 mL). The mixture stirred for 30 minutes and wasacidified to pH 6 with 2 N HCl. The mixture was concentrated underreduce pressure and the residue was added to a separate of mixture4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.068 g, 0.257mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.227 g, 0.514 mmol), and i-Pr₂NEt (0.100 g, 0.771mmol) in DMF (2 mL). The mixture was stirred at ambient temperature for16 hours and was poured into H₂O. The mixture was extracted with EtOAc(30 mL) and the organic layer was washed with brine (2×30 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting residue was chromatographed over silica gel (0-40% EtOAc inhexanes) and freeze dried to give(6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.036 g, 34%): mp158-160° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.27 (m, 1H), 7.84 (m, 1H), 7.66(d, J=7.8 Hz, 1H), 7.55-7.30 (m, 4H), 5.73-5.68 (m, 1H), 5.00-4.94 (m,1H), 3.39-3.28 (m, 2H), 3.03-2.93 (m, 1H), 2.04-1.76 (m, 4H); MS (ESI+)m/z 409 [M+H]⁺.

Example 13: Preparation of(6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A solution of 2-hydrazinyl-5-(trifluoromethyl)pyridine (0.525 g,2.96 mmol) and ethyl 2-oxoacetate (50% in toluene, 0.604 g, 2.96 mmol)in CH₃OH (20 mL) was heated at 60° C. for 1 hour, then cooled to ambienttemperature and concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂ (20 mL) to which PhI(OAc)₂ (0.953 g, 2.96 mmol) wasadded and the mixture was stirred for 2 hours. The mixture wasconcentrated under reduced pressure and the residue was chromatographedover silica gel (0-50% EtOAc in hexanes) to give ethyl6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate as anyellow solid (0.626 g, 81%): ¹H NMR (300 MHz, CDCl₃) δ 9.57 (m, 1H),8.08 (d, J=9.6 Hz, 1H), 7.63 (dd, J=9.6, 1.6 Hz, 1H), 4.62 (q, J=7.1 Hz,2H), 1.53 (t, J=7.1 Hz, 3H).

Step B: To a solution of ethyl6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.067g, 0.259 mmol) in THF (3 mL) was added a solution LiOH monohydrate(0.033 g, 0.777 mmol) in H₂O (1 mL). The mixture was stirred for 30minutes then acidified to pH 6 with 2 N HCl and concentrated underreduced pressure. The resulting residue was added to a mixture of4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.069 g, 0.259mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.228 g, 0.516 mmol), and i-Pr₂NEt (0.100 g, 0.777mmol) in DMF (2 mL). The mixture was stirred at ambient temperature for16 hours and poured into H₂O. The mixture was extracted with EtOAc (30mL) and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0-40% EtOAc in hexanes) andfreeze dried to give(6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.042 g, 36%): mp 144-146° C.; ¹H NMR (300 MHz, CDCl₃)δ 9.60 (m, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H),7.59-7.43 (m, 3H), 7.33 (t, J=7.5 Hz, 1H), 5.73-5.68 (m, 1H), 5.01-4.96(m, 1H), 3.41-3.32 (m, 2H), 3.05-2.96 (m, 1H), 2.06-1.78 (m, 4H); MS(ESI+) m/z 443 [M+H]⁺.

Example 14: Preparation of(6-Ethoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A solution of 5-ethoxy-2-hydrazinylpyridine (0.460 g, 3.00 mmol)and ethyl 2-oxoacetate (50% in toluene, 0.613 g, 3.00 mmol) in CH₃OH (20mL) was heated at 60° C. for 1 hour, cooled to ambient temperature andconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂(20 mL). PhI(OAc)₂ (1.06 g, 3.30 mmol) was added and the mixture wasstirred for 2 hours and concentrated under reduced pressure. The residuewas chromatographed over silica gel (0-80% EtOAc in hexanes) to giveethyl 6-ethoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate as an yellowsolid (0.620 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J=1.7 Hz, 1H),7.84 (dd, J=9.8, 0.7 Hz, 1H), 7.26 (dd, J=9.8, 2.2 Hz, 1H), 4.57 (q,J=7.1 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.54-1.48 (m, 6H); MS (ESI+) m/z236 [M+H]⁺.

Step B: To a solution of ethyl6-ethoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.072 g, 0.306mmol) in THF (3 mL) was added a solution of lithium hydroxide hydrate(0.038 g, 0.918 mmol) in H₂O (1 mL). The mixture was stirred for 30 min,acidified to pH 6 with 2 N HCl and concentrated under reduced pressure.The resulting residue were added to a mixture of4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (5, 0.081 g, 0.306mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.271 g, 0.612 mmol), and i-Pr₂NEt (0.119 g, 0.918mmol) in DMF (2 mL). The mixture Was stirred at ambient temperature for16 hours and poured into H₂O. The mixture was extracted with EtOAc (30mL) and the organic layer was washed with brine (2×30 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0-30% EtOAc in hexanes) andfreeze dried to give (6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl) phenyl)piperidin-1-yl)methanone as an off-whitesolid (0.068 g, 53%): mp 113-115° C.; ¹H NMR (300 MHz, CDCl₁) δ 8.68 (d,J=1.8 Hz, 1H), 7.76 (m, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.54-7.44 (m, 2H),7.34-7.19 (m, 2H), 5.78-5.73 (m, 1H), 4.96 (m, 1H), 4.12-4.04 (m, 2H),3.37-2.29 (m, 2H), 3.01-2.92 (m, 1H), 2.03-1.76 (m, 4H), 1.48 (t, J=7.2Hz, 3H); MS (ESI+) m/z 419 [M+H]⁺.

Example 15: Preparation of(5-Fluoro-1H-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and5-fluoro-1H-indazole-3-carboxylic acid were converted to(5-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.087 g, 51%): mp 188-190° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.64 (s, 1H), 7.73-7.59 (m, 5H), 7.45-7.39 (m, 1H),7.36-7.29 (m, 1H), 5.08-4.99 (m, 1H), 4.83-4.74 (m, 1H), 3.29-3.13 (m,2H), 2.95-2.85 (m, 1H), 1.86-1.71 (m, 4H); ESI MS m/z 392 [M+H]⁺.

Example 16: Preparation of(4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneHydrochloride

Step A: To a solution of(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(6, 0.045 g, 0.12 mmol) in CH₃OH (1.0 mL) was added HCl (2N in Et₂O,0.060 mL, 0.12 mmol) the reaction was stirred at ambient temperature for30 min. The reaction was diluted with Et₂O (20 ml) and the solidscollected by filtration to provide(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone hydrochloride as a white solid (10,0.031 g, 63%): mp 272-278° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 13.32 (s,1H), 9.47 (s, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.65-7.60 (m, 2H), 7.45-7.38(m, 1H), 5.32-5.27 (m, 1H), 4.72-4.64 (m, 1H), 4.27-4.16 (m, 2H), 3.35(t, J=6.0 Hz, 2H), 3.24-3.20 (m, 2H), 2.96 (t, J=5.5 Hz, 2H), 2.86-2.75(m, 1H), 1.82-1.63 (m, 4H); ESI MS m/z 379 [M+H]⁺.

Example 17: Preparation of1-(3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone

Step A: Following general procedure GP-E,(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand acetyl chloride were converted to(1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanoneas a white solid (0.032 g, 71%): mp 202-209° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.99-12.91 (m, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.65-7.60 (m,2H), 7.44-7.38 (m, 1H), 5.31-5.12 (m, 1H), 4.47-4.46 (m, 3H), 3.80-3.61(m, 2H), 3.20-3.09 (m, 2H), 2.85-2.75 (m, 2H), 2.65 (t, J=5.5 Hz, 1H),2.11-2.05 (m, 3H), 1.82-1.65 (m, 4H); ESI MS m/z 421 [M+H]⁺.

Example 18: Preparation of(6-(Methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-F,(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand methane sulfonylchloride were converted to(6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.034 g, 70%): mp 242-245° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.03 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.64-7.60 (m, 2H),7.43-7.39 (m, 1H), 5.30-5.21 (m, 1H), 4.72-4.64 (m, 1H), 4.43-4.27 (m,2H), 3.51-3.41 (m, 2H), 3.21-3.09 (m, 2H), 3.94 (s, 3H), 2.86-2.75 (m,3H), 1.81-1.64 (m, 4H); ESI MS m/z 457 [M+H]⁺.

Example 19: Preparation of(6-Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-G,(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand 37% aqueous formaldehyde were converted to(6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.008 g, 13%): mp 115-120° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.83 (br s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.65-7.59 (m, 2H),7.45-7.38 (m, 1H), 5.15-5.07 (m, 2H), 4.71-4.63 (m, 2H), 3.62-3.40 (m,2H), 3.18-3.07 (m, 2H), 2.83-2.65 (m, 4H), 2.47-2.38 (m, 2H), 1.83-1.62(m, 4H); ESI MS m/z 393 [M+H]⁺.

Example 20: Preparation of(6-Fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methadone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-fluoro-1H-indazole-3-carboxylic acid were converted to(6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.053 g, 31%): mp 210-212° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 13.54 (s,1H), 8.04-8.01 (m, 1H), 7.71-7.60 (m, 3H), 7.44-7.39 (m, 2H), 7.13-7.10(m, 1H), 4.96-4.78 (m, 2H), 3.25-3.17 (m, 2H), 2.92-2.90 (m, 1H),1.82-1.77 (m, 4H); ESI MS m/z 392 [M+H]⁺.

Example 21: Preparation of(5-Fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and5-fluoro-1-methyl-1H-indazole-3-carboxylic acid were converted to(5-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.079 g, 44%): mp 161-163° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.90-7.20(m, 4H), 7.45-7.43 (m, 2H), 7.26-7.20 (m, 1H), 4.68 (br s, 1H), 4.22 (brs, 3H), 3.76-3.48 (m, 2H), 3.13-3.02 (m, 2H), 2.01-1.57 (m, 4H); ESI MSm/z 406 [M+H]⁺.

Example 22: Preparation of 1-(3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step A: To a solution of 4-(2-(trifluoromethyl)phenyl)piperidin-4-ol(1.00 g, 4.08 mmol) in CH₂Cl₂ (25 mL) and i-Pr₂NEt (1.0 mL, 5.74 mmol)was added di-tert-butyl dicarbonate (1.07 g 4.90 mmol) and the reactionstirred at ambient temperature for 4 hours. The reaction was dilutedwith aqueous saturated NH₄Cl and extracted with CH₂Cl₂ (2×25 mL). Thecombined organic extracts were washed with H₂O, dried over MgSO₄,filtered, and concentrated under reduced pressure to provide tert-butyl4-hydroxy-4-(2-(trifluoromethyl) phenyl)piperidine-1-carboxylate as anoff-white solid (1.20 g, 85%): ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=7.8Hz, 1H), 7.53-7.51 (m, 2H), 7.40-7.34 (m, 1H), 4.09-4.02 (m, 2H),3.31-3.20 (m, 2H), 2.16-2.05 (m, 2H), 1.96-1.77 (m, 3H), 1.48 (s, 9H).

Step B: To a solution of tert-butyl4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.400g, 1.16 mmol) in CH₂Cl₂ (12 mL) stirring at −50° C. was addedDeoxo-Flour® (0.26 mL, 1.41 mmol) dropwise over 20 min. The reaction wasslowly warmed to room temperature over a period of 16 hours. Thereaction was quenched with a saturated aqueous solution of Na₂CO₄ (20mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organic extractswere washed with H₂O, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was chromatographed over silicagel (Isco CombiFlash Companion unit, 40 g Redisep column, 0-100% EtOAcin hexanes) to provide tert-butyl4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxylate as aclear liquid (0.205 g, 51%): NMR (300 MHz, CDCl₃) δ 7.79 (d, J=7.8 Hz,1H), 7.53-7.51 (m, 2H), 7.40-7.34 (m, 1H), 4.09-4.02 (m, 2H), 3.31-3.20(m, 2H), 2.16-2.05 (m, 2H), 1.96-1.77 (m, 38), 1.48 (s, 9H).

Step C: To a solution of tert-butyl4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.205 g,0.59 mmol) in CH₂Cl₂ (2 mL) was added a solution of 2 M HCl in Et₂O (2mL) and the solution stirred for 6 hours at ambient temperature. Themixture was concentrated under reduced pressure to provide4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride as anoff-white solid (0.153 g, 92%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.15-8.90(m, 1H), 7.88-7.51 (m, 4H), 3.40-3.02 (m, 6H), 2.22-2.14 (m, 2H); ESI MSm/z 248 [M+H]⁺.

Step D: To a solution of 4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (0.128 g, 0.45 mmol),5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (0.130 g, 0.50 mmol), and i-Pr₂NEt (0.24 mL, 1.38 mmol) in DMF (10mL) was added EDCI (0.120 g, 0.63 mmol) and HOBt (0.085 g, 0.63 mmol).The mixture stirred for 18 hours at ambient temperature and was dilutedwith H₂O (10 mL). The aqueous mixture was extracted with EtOAc (3×10 mL)and the combined organic extracts were washed with brine (10 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresulting residue was chromatographed over silica gel (Isco CombiFlashCompanion unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) toprovide tert-butyl3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylateas a white solid (0.121 g, 54%): ¹H NMR (300 MHz, CDCl₃) δ 7.82-7.79 (m,1H), 7.56-7.40 (m, 3H), 4.77 (br s, 1H), 4.62 (s, 2H), 3.74-3.12 (m,6H), 2.82-2.78 (m, 2H), 2.33-2.18 (m, 4H), 1.48 (s, 9H); ESI MS m/z 497[M+H]⁺.

Step E: To a solution of tert-butyl 3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(0.121 g, 0.24 mmol) in CH₂Cl₂ (3 mL) was added a solution of 2 M HCl inEt₂O (1.2 mL) and the mixture was stirred for 7 hours at ambienttemperature. The solvent was removed under reduced pressure and theresidue was triturated with hexanes to provide(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanonehydrochloride as a white solid (0.076 g, 73%): ¹H NMR (300 MHz, DMSO-d₆)δ 13.31 (br s, 1H), 9.19 (br s, 1H), 7.86-7.83 (m, 1H), 7.68-7.66 (m,2H), 7.58-7.54 (m, 1H), 5.26-5.22 (m, 1H), 4.61-4.57 (m, 1H), 4.25 (s,2H), 3.51-3.35 (m, 4H), 3.11-2.91 (m, 3H), 2.32-2.07 (m, 4H).

Step F: To a solution of (4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanonehydrochloride (0.076 g, 0.19 mmol) in DMF (2 mL) and i-Pr₂NEt (0.08 mL,0.46 mmol) was added acetyl chloride (0.014 mL, 0.20 mmol) and thereaction stirred for 18 hours at ambient temperature. The reaction wasconcentrated under reduced pressure and the residue was dissolved in asolution of 7 M NH, in CH₃OH (4 mL). The mixture stirred at ambienttemperature for 30 minutes and was concentrated under reduced pressure.The resulting residue was chromatographed over silica gel (IscoCombiFlash Companion unit, 12 g Redisep column, 0% to 100% (90:10:0.01CH₂Cl₂, CH₃OH, NH₄OH in CH₂Cl₂) and dried in at 60° C. under vacuum toprovide1-(3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneas a white solid (0.031 g, 39%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.04-13.00(m, 1H), 7.85-7.82 (m, 1H), 7.69-7.53 (m, 3H), 5.20-5.12 (m, 1H),4.59-4.48 (m, 3H), 3.82-3.62 (m, 2H), 3.46-3.37 (m, 1H), 3.08-3.02 (m,1H), 2.83-2.59 (m, 2H), 2.27-2.06 (m, 7H); ESI MS m/z 439 [M+H]⁺.

Example 23: Preparation of(6-Fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluormethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of(6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.05 g, 0.13 mmol) and iodopropane (0.020 mL, 0.19 mmol) in DMF (2 mL)was added K₂CO₃ (0.044 g, 0.32 mmol). The mixture stirred for 4 hours atambient temperature and was then diluted with H₂O (5 mL). The aqueousmixture was extracted with EtOAc (5 mL) and the organic extracts weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The resulting residue was chromatographed over silica gel (Parallex Flexunit, YMC-Pack ODS-A column, 5% to 95% CH₂CN in H₂O) to give(6-fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoro-methyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.032 g, 58%): mp=50-53° C.; ¹H NMR (500 MHz, CDCl₂) δ7.85 (dd, J=2.4 Hz, J=8.9 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.52 (t,J=7.7 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.40 (dd, J=4.0 Hz, J=9.1 Hz,1H), 7.31 (t, J=7.6 Hz, 1H), 7.18 (dt, J=2.5 Hz, J=8.9 Hz, 1H), 5.09 (brs, 2H), 4.89-4.80 (m, 1H), 3.32-2.94 (m, 3H), 1.93-1.81 (m, 4H), 1.59(d, J=6.7 Hz, 6H); MS (APCI+) m/z 434 [M+H]⁺.

Example 24: Preparation of(1-Ethyl-6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of(6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.05 g, 0.13 mmol) and iodoethane (0.015 mL, 0.19 mmol) in DMF (2 mL)was added K₂CO₃ (0.044 g, 0.32 mmol). The mixture stirred for 4 hours atambient temperature and was then diluted with H₂O (5 mL). The aqueousmixture was extracted with EtOAc (5 mL) and the organic extracts weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The resulting residue was chromatographed over silica gel (Parallax Flexunit, YMC-Pack ODS-A column, 5% to 95% CH₃CN in H₂O) to give(1-ethyl-6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl) phenyl)piperidin-1-yl)methanone as a white solid (0.020 g, 37%): mp=44-46° C.;¹H NMR (500 MHz, CDCl₃) δ 7.83 (dd, J=2.4 Hz, J=8.9 Hz, 1H), 7.64 (d,J=7.7 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.37 (dd,J=4.0 Hz, J=9.1 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.20 (dt, J=2.4 Hz,J=8.9 Hz, 1H), 5.07 (d, J=47.2 Hz, 2H), 4.44 (q, J=7.3 Hz, 2H),3.38-3.24 (m, 2H), 2.93 (br s, 1H), 1.99-1.81 (m, 4H), 1.54 (t, J=7.3Hz, 3H); MS (APCI+) m/z 420 [M+H]⁺.

Example 25: Preparation of(6-Fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of(6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.075 g, 0.19 mmol) and 3-iodooxetane (0.025 mL, 0.29 mmol) in DMF (2mL) was added K₂CO₃ (0.066 g, 0.48 mmol). The mixture stirred for 24 hat ambient temperature and 3-iodooxetane (0.015 mL, 0.19 mmol) was addedand stirred at 60° C. for 24 hours. The mixture was diluted with H₂O (5mL). The aqueous mixture was extracted with EtOAc (5 mL) and the organicextracts were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was chromatographed over silicagel (Parallex Flex unit, YMC-Pack ODS-A column, 5% to 95% CH₂CN in H₂O)to give(6-fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.023 g, 27%): mp=70-73° C.; ¹H NMR (500 MHz, CDCl₃) δ7.86 (dd, J=2.2 Hz, J=8.8 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.54-7.45 (m,3H), 7.32 (t, J=7.7 Hz, 1H), 7.23 (dd, J=2.5 Hz, J=8.9 Hz, 1H),5.82-5.76 (m, 1H), 5.25 (t, J=6.6 Hz, 2H), 5.16-5.11 (m, 3H), 5.02 (d,J=12.1 Hz, 1H), 3.34-3.27 (m, 2H), 2.97-2.94 (m, 1H), 2.05-1.81 (m, 4H);MS (APCI+) m/z 448 [M+H]⁺.

Example 26: Preparation of(4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of tert-butyl3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(0.600 g, 1.25 mmol) in CH₂Cl₂ (5 mL) was added TFA (2 mL). The mixturewas concentrated under reduced pressure and further co-evaporated withCH₂Cl₂ (3×10 mL) and CH₂CN (3×10 mL). The resulting residue wassuspended in CH₃OH (50 mL) and 1N HCl (10 mL) was then added. Theresulting solution was concentrated under reduced pressure and theresidue obtained was again suspended in CH₃OH (50 mL) and 1N HCl (10 mL)was then added. The resulting solution was concentrated under reducedpressure and the solid obtained was triturated with CH₃OH/CH₂CN to give(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (12, 0.332 g, 59%): mp=270-272° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.26 (s, 1H), 9.18 (s, 2H), 7.69 (d, J=7.9 Hz, 1H), 7.62 (s,2H), 7.44-7.40 (m, 1H), 5.28 (d, J=12.3 Hz, 1H), 4.68 (d, J=11.4 Hz,1H), 4.24 (d, J=5.7 Hz, 2H), 3.38 (t, J=5.8 Hz, 2H), 3.20-3.11 (m, 2H),2.95 (t, J=5.8 Hz, 2H), 2.82 (t, J=12.4 Hz, 1H), 1.85-1.63 (m, 4H); MS(APCI+) m/z 379 [M+H]⁺.

Example 27: Preparation of1-(3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step A: Following general procedure GP-B,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand acetyl chloride were converted to1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneas a white solid (0.031 g, 66%): mp=208-211° C.; ¹H NMR (500 MHz,DMSO-d₆) δ12.96 (d, J=20.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.66-7.62(m, 2H), 7.43-7.38 (m, 1H), 5.22 (d, J=38.7 Hz, 1H), 4.75-4.46 (m, 3H),3.82-3.61 (m, 2H), 3.20-3.11 (m, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.66 (t,J=5.6 Hz, 1H), 2.08 (d, J=12.7 Hz, 3H), 1.83-1.68 (m, 4H); MS (APCI+)m/z 421 [M+H]⁺.

Example 28: Preparation of(5-(Methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand methane sulfonyl chloride were converted to(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.040 g, 79%): mp=240-243° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.03 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.66-7.60 (m, 2H),7.45-7.39 (m, 1H), 5.26 (d, J=10.2 Hz, 1H), 4.69 (d, J=10.6 Hz, 1H),4.42-4.21 (m, 2H), 3.51-3.44 (m, 2H), 3.19-3.11 (m, 2H), 2.94 (s, 3H),2.86-2.79 (m, 3H), 1.86-1.63 (m, 4H); MS (APCI+) m/z 457 [M+H]⁺.

Example 29: Preparation of((6-Chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-chloro-1H-indazole-3-carboxylic acid were converted to(6-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.034 g, 22%): mp=221-223° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 13.64 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.72-7.60 (m, 4H),7.42 (t, J=7.4 Hz, 1H), 7.26 (dd, J=1.7 Hz, J=8.7 Hz, 1H), 4.94 (d, J13.5 Hz, 1H), 4.79 (d, J 12.1 Hz, 1H), 3.32-3.11 (m, 2H), 2.91 (t, J=9.6Hz, 1H), 1.89-1.70 (m, 4H); MS (APCI+) m/z 408 [M+H]⁺.

Example 30: Preparation of(1H-pyrazolo[3,4-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid were converted to(1H-pyrazolo[3,4-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.058 g, 41%): mp=202-205° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 13.92 (s, 1H), 9.33 (s, 1H), 8.42 (d, J=5.9 Hz, 1H),7.75-7.60 (m, 4H), 7.43 (t, J=7.4 Hz, 1H), 4.96 (d, J=13.2 Hz, 1H), 4.80(d, J=12.9 Hz, 1H), 3.29-3.14 (m, 2H), 3.01-2.89 (m, 1H), 1.89-1.73 (m,4H); MS (APCI+) m/z 375 [M+H]⁺.

Example 31: Preparation of(5-Chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and5-chloro-1H-indazole-3-carboxylic acid were converted to(5-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a light pink solid (0.054 g, 35%): mp=210-212° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 13.73 (s, 1H), 8.05 (s, 1H), 7.75-7.62 (m, 4H), 7.48-7.39 (m,2H), 5.03 (d, J=12.8 Hz, 1H), 4.79 (d, J=11.8 Hz, 1H), 3.29-3.17 (m,2H), 2.99-2.87 (m, 1H), 1.81 (t, J=6.9 Hz, 4H); MS (APCI+) m/z 408[M+H]⁺.

Example 32s Preparation of(5-Methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and5-methoxy-1H-indazole-3-carboxylic acid were converted to(5-methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.078 g, 51%): mp=168-170° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.75 (s, 1H), 7.69-7.62 (m, 3H), 7.42 (t, J=6.3 Hz, 1H), 7.34(d, J=2.9 Hz, 1H), 7.28 (d, J=8.9 Hz, 1H), 7.22 (dd, J=2.9 Hz, J=8.9 Hz,1H), 4.24 (d, J=13.5 Hz, 2H), 3.79 (s, 3H), 3.09 (t, J=11.4 Hz, 1H),2.94 (t, J=11.8 Hz, 2H), 1.86-1.68 (m, 4H); MS (APCI+) m/z 404 [M+H]⁺.

Example 33: Preparation ofBenzo[c]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and3-carboxy-2,1-benzisoxazole were converted tobenzo[c]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.093 g, 66%): mp=106-108° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 7.86 (d, J=8.9 Hz, 1H), 7.45 (t, J=9.1 Hz, 2H), 7.70-7.63 (m,2H), 7.52-7.48 (m, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.28-7.24 (m, 1H),4.74-4.65 (m, 1H), 4.27-4.18 (m, 1H), 3.50-3.38 (m, 1H), 3.24-3.17 (m,1H), 3.09-3.00 (m, 1H), 1.98-1.75 (m, 4H); MS (APCI+) m/z 375 [M+H]⁺.

Example 34: Preparation of(5,6-Difluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and5,6-difluoro-1H-indazole-3-carboxylic acid were converted to(5,6-difluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.074 g, 48%): mp=233-235° C.; ¹H NMR (500 MHz,DMSO-de) δ 13.72 (s, 1H), 7.96-7.91 (m, 1H), 7.74-7.67 (m, 3H),7.66-7.60 (m, 1H), 7.44-7.39 (m, 1H), 5.02 (d, J=12.1 Hz, 1H), 4.78 (d,J=11.1 Hz, 1H), 3.29-3.17 (m, 2H), 2.91 (t, J=12.0 Hz, 1H), 1.86-1.74(m, 4H); MS (APCI+) m/z 410 [M+H]⁺.

Example 35: Preparation of(7-Chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and7-chloro-1H-indazole-3-carboxylic acid were converted to(7-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.100 g, 65%): mp=192-195° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 14.03 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.69 (d, J=8.2 Hz,2H), 7.64 (t, J=7.4 Hz, 1H), 7.53 (d, J=6.8 Hz, 1H), 7.42 (t, J=7.8 Hz,1H), 7.24 (t, J=7.5 Hz, 1H), 4.87 (d, J=13.0 Hz, 1H), 4.79 (d, J=12.7Hz, 1H), 3.29-3.16 (m, 2H), 3.03-2.83 (m, 1H), 1.89-1.70 (m, 4H); MS(APCI+) m/z 408 [M+H]⁺.

Example 36: Preparation of 3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-1H-indazole-5-carbonitrile

Step A: To a solution of(5-bromo-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.100 g, 0.22 mmol) and CuCN (0.040 g, 0.44 mmol) was added NMP (1 mL).The mixture stirred for 48 hours at 160° C., and was then diluted with 6N HCl (3 mL) and stirred at ambient temperature for 10 minutes. Themixture was then diluted with H₂O (10 mL) and extracted with CH₂Cl₂ (10mL) and the organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue waschromatographed over silica gel (Isco CombiFlash Companion unit, 12 gRedisep column, 0% to 20% EtOAc in hexanes) then purified by preparativeTLC (0% to 3% EtOAc in hexanes) to give3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1H-indazole-5-carbonitrileas a white solid (0.019 g, 22%): mp=249-252° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 14.01 (s, 1H), 8.52 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.75 (d,J=8.7 Hz, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.64 (t, J 7.4 Hz, 1H), 7.42 (t,J=7.4 Hz, 1H), 4.92 (d, J=13.5 Hz, 1H), 4.79 (d, J=11.5 Hz, 1H),3.25-3.17 (m, 2H), 3.03-2.91 (m, 1H), 1.87-1.72 (m, 4H); MS (APCI+) m/z399 [M+H]⁺.

Example 37: Preparation of(5-(Ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand ethane sulfonyl chloride were converted to(5-(ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.038 g, 48%): mp=187-189° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.03 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.66-7.61 (m, 2H),7.43-7.38 (m, 1H), 5.27 (d, J=11.8 Hz, 1H), 4.68 (d, J=11.6 Hz, 1H),4.48-4.33 (m, 2H), 3.59-3.47 (m, 2H), 3.20-3.08 (m, 4H), 2.88-2.74 (m,3H), 1.82-1.63 (m, 4H), 1.21 (t, J=7.4 Hz, 3H); MS (APCI+) m/z 471[M+H]⁺.

Example 38: Preparation of(5-(Isobutylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand isobutane sulfonyl chloride were converted to(5-(isobutylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.047 g, 57%): mp=178-180° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.03 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.64-7.61 (m, 2H),7.44-7.38 (m, 1H), 5.26 (d, J=11.8 Hz, 1H), 4.68 (d, J=11.3 Hz, 1H),4.45-4.30 (m, 2H), 3.56-3.43 (m, 2H), 3.21-3.12 (m, 2H), 2.98 (d, J=6.6Hz, 2H), 2.80 (t, J=5.6 Hz, 3H), 2.17-2.06 (m, 1H), 1.82-1.63 (m, 4H),1.04 (d, J=6.8 Hz, 6H); MS (APCI+) m/z 499 [M+H]⁺.

Example 39z Preparation of(5-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand isopropyl sulfonyl chloride were converted to(5-(isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas an off-white solid (0.022 g, 27%): mp=199-201° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.02 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.66-7.59 (m, 2H),7.44-7.38 (m, 1H), 5.28 (d, J=12.3 Hz, 1H), 4.68 (d, J=9.6 Hz, 1H),4.53-4.36 (m, 2H), 3.62-3.56 (m, 2H), 3.42-3.36 (m, 1H), 3.11-3.08 (m,2H), 2.83-2.74 (m, 3H), 1.87-1.63 (m, 4H), 1.23 (d, J=6.8 Hz, 6H); MS(APCI+) m/z 485 [M+H]⁺.

Example 40: Preparation of2,2-Dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-one

Step A: Following general procedure GP-B,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand pivaloyl chloride were converted to2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-oneas a white solid (11, 0.065 g, 85%): mp 126-128° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.95 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.62 (d, J=3.3 Hz,2H), 7.44-7.39 (m, 1H), 5.24 (d, J=9.5 Hz, 1H), 4.78-4.57 (m, 3H),3.82-3.74 (m, 2H), 3.19-3.10 (m, 2H), 2.88-2.74 (m, 1H), 2.71 (t, J=5.6Hz, 2H), 1.83-1.67 (m, 4H), 1.22 (s, 9H); MS (APCI+) m/z 463 [M+H]⁺.

Example 41; Preparation of 2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-one

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand isobutyryl chloride were converted to2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-oneas a white solid (0.053 g, 71%): mp=112-114° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.96 (d, J=17.3 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.63 (d,J=5.3 Hz, 2H), 7.41 (t, J=5.4 Hz, 1H), 5.21 (d, J 37.7 Hz, 1H),4.72-4.50 (m, 3H), 3.79-3.68 (m, 2H), 3.21-3.11 (m, 2H), 2.99-2.88 (m,1H), 2.87-2.65 (m, 2H), 2.68-2.60 (m, 1H), 1.84-1.67 (m, 4H), 1.02 (dd,J=6.7 Hz, J=17.9 Hz, 6H); MS (APCI+) m/z 449 [M+H]⁺.

Example 42: Preparation of 3-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)butan-1-one

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand isovaleryl chloride were converted to3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)butan-1-oneas a white solid (0.054 g, 70%): mp=107-109° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.95 (d, J=19.2 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.64-7.61(m, 2H), 7.41 (t, J=7.8 Hz, 1H), 5.26-5.15 (m, 1H), 4.71-4.53 (m, 3H),3.75-3.66 (m, 2H), 3.17-3.12 (m, 2H), 2.88-2.73 (m, 2H), 2.70-2.61 (m,1H), 2.27 (dd, J=6.9 Hz, J=19.9 Hz, 2H), 2.09-1.93 (m, 1H), 1.82-1.66(m, 4H), 0.90 (dd, J=6.7 Hz, J=9.7 Hz, 6H); MS (APCI+) m/z 463 [M+H]⁺.

Example 43: Preparation of(5-Ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-D,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand acetaldehyde were converted to(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.018 g, 41%):mp=159-162° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.76 (s, 1H), 7.68 (d,J=7.9 Hz, 1H), 7.62 (d, J=3.9 Hz, 2H), 7.45-7.39 (m, 1H), 5.08 (d,J=10.7 Hz, 1H), 4.67 (d, J=11.3 Hz, 1H), 3.55-3.41 (m, 2H), 3.17-3.09(m, 2H), 2.80-2.75 (m, 1H), 2.73-2.62 (m, 4H), 2.55-2.53 (m, 2H),1.80-1.66 (m, 4H), 1.07 (t, J=7.1 Hz, 3H); MS (APCI+) m/z 407 [M+H]⁺.

Example 44: Preparation of 1-(3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-one

Step A: Following general procedure GP-B,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand propionyl chloride were converted to1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-oneas a white solid (0.053 g, 73%): mp=153-155° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.95 (d, J=20.2 Hz, 1H), 7.73-7.64 (m, 3H), 7.48-7.37 (m,1H), 5.32-5.14 (m, 1H), 4.71-4.53 (m, 3H), 3.76-3.67 (m, 2H), 3.21-3.14(m, 2H), 2.89-2.61 (m, 3H), 2.46-2.35 (m, 2H), 1.88-1.67 (m, 4H),1.05-0.98 (m, 3H); MS (APCI+) m/z 435 [M+H]⁺.

Example 45: Preparation of(5-Isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-D,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand isobutyraldehyde were converted to(5-isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.068 g, 71%): mp=105-107° C.; NMR (500 MHz, DMSO-d₆)δ 12.77 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.63-7.60 (m, 2H), 7.43-7.39(m, 1H), 5.12-5.08 (m, 1H), 4.69-4.65 (m, 1H), 3.51-3.44 (m, 2H),3.19-3.10 (m, 2H), 2.83-2.72 (m, 1H), 2.70-2.61 (m, 4H), 2.24 (d, J=7.3Hz, 2H), 1.89-1.63 (m, 5H), 0.88 (d, J=6.6 Hz, 6H); MS (APCI+) m/z 435[M+H]⁺.

Example 46: Preparation of(5-(Oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand 3-oxetanone were converted to(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.023 g, 24%): mp=107-110° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.82 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.64-7.60 (m, 2H),7.43-7.38 (m, 1H), 5.18-5.09 (m, 1H), 4.70-4.58 (m, 3H), 4.53-4.46 (m,2H), 3.71-3.64 (m, 1H), 3.45-3.34 (m, 2H), 3.28 (s, 2H), 3.18-3.07 (m,2H), 2.84-2.68 (m, 3H), 1.80-1.63 (m, 4H); MS (APCI+) m/z 435 [M+H]⁺.

Example 47: Preparation of3,3,3-Trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-one

Step A: Following general procedure GP-B,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand 3,3,3-trifluoropropanoyl chloride were converted to3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propan-1-oneas a white solid (0.020 g, 23%): mp=127-130° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.98 (d, J=15.7 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.66-7.60(m, 2H), 7.42-7.38 (m, 1H), 5.28-5.15 (m, 1H), 4.73-4.52 (m, 3H),3.89-3.65 (m, 4H), 3.20-3.11 (m, 2H), 2.85-2.63 (m, 3H), 1.85-1.67 (m,4H); MS (APCI+) m/z 469 [M+H]⁺.

Example 46: Preparation of2-Methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone

Step A: Following general procedure GP-C,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand 2-methoxyacetyl chloride were converted to2-methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanoneas a white solid (0.029 g, 35%): mp=192-194° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.97 (d, J=13.7 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.64-7.61(m, 2H), 7.44-7.38 (m, 1H), 5.39-5.14 (m, 1H), 4.75-4.48 (m, 3H), 4.16(d, J=17.1 Hz, 2H), 3.81-3.59 (m, 2H), 3.32-3.28 (m, 3H), 3.24-3.10 (m,2H), 2.88-2.65 (m, 3H), 1.83-1.65 (m, 4H); MS (APCI+) m/z 451 [M+H]⁺.

Example 49: Preparation of 1-(3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)propan-1-one

Step A: Following general procedure GP-E,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand propionyl chloride were converted to1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)propan-1-oneas a white solid (0.019 g, 40%): mp=162-164° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.95 (d, J=20.4 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.65-7.61(m, 2H), 7.44-7.38 (m, 1H), 5.31-5.13 (m, 14), 4.76-4.49 (m, 3H),3.78-3.64 (m, 2H), 3.19-3.11 (m, 2H), 2.85-2.75 (m, 24), 2.68-2.62 (m,1H), 2.45-2.34 (m, 24), 1.83-1.65 (m, 4H), 1.01 (d, J=7.3 Hz, 34); MS(APCI+) m/z 435 [M+H]⁺.

Example 50: Preparation of(6-(Ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-F,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand ethane sulfonyl chloride were converted to(6-(ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.036 g, 69%): mp=209-211° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.03 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.64-7.61 (m, 2H),7.44-7.40 (m, 1H), 5.27 (d, J=11.5 Hz, 1H), 4.68 (d, J=11.6 Hz, 1H),4.43-4.34 (m, 2H), 3.54-3.50 (m, 2H), 3.19-3.09 (m, 4H), 2.79 (t, J=5.6Hz, 3H), 1.80-1.62 (m, 4H), 1.21 (t, J=7.4 Hz, 3H); MS (APCI+) m/z 471[M+H]⁺.

Example 51: Preparation of(6-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-F,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand isopropyl sulfonyl chloride were converted to(6-(isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.014 g, 26%): mp=220-222° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.02 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.64-7.60 (m, 2H),7.44-7.39 (m, 1H), 5.33-5.22 (m, 1H), 4.71-4.64 (m, 1H), 4.55-4.38 (m,2H), 3.62-3.56 (m, 2H), 3.46-3.38 (m, 1H), 3.19-3.11 (m, 2H), 2.83-2.74(m, 3H), 1.82-1.64 (m, 4H), 1.23 (d, J=6.8 Hz, 6H); MS (APCI+) m/z 485[M+H]⁺.

Example 52: Preparation of 2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)propan-1-one

Step A: Following general procedure GP-E,(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneand isobutyryl chloride were converted to2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)propan-1-oneas a white solid (0.045 g, 91%): mp=200-203° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.96 (d, J=17.2 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.64-7.61(m, 2H), 7.43-7.38 (m, 1H), 5.28-5.13 (m, 1H), 4.77-4.48 (m, 3H),3.80-3.69 (m, 2H), 3.19-3.10 (m, 2H), 2.98-2.88 (m, 1H), 2.83-2.73 (m,2H), 2.70-2.62 (m, 1H), 1.82-1.68 (m, 4H), 1.02 (dd, J=6.7 Hz, J=11.2Hz, 6H); MS (APCI+) m/z 449 [M+H]⁺.

Example 53: Preparation of 1-(3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)propan-1-one

Step A: Following general procedure GP-H,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (14) and propionyl chloride wereconverted to1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)propan-1-oneas a white solid (0.067 g, 93%): mp=216-219° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.26 (d, J=92.8 Hz, 1H), 7.73-7.62 (m, 3H), 7.45-7.40 (m,1H), 4.71-4.40 (m, 5H), 3.31 (s, 2H), 3.25-2.78 (m, 2H), 2.39-2.33 (m,2H), 1.86-1.67 (m, 4H), 1.03 (t, J=7.4 Hz, 3H); MS (APCI+) m/z 421[M+H]⁺.

Example 54: Preparation of 2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)propan-1-one

Step A: Following general procedure GP-H,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (14) and isobutyryl chloride wereconverted to2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)propan-1-oneas a white solid (0.070 g, 93%): mp=192-195° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.26 (d, J=95.0 Hz, 1H), 7.73-7.61 (m, 3H), 7.45-7.39 (m,1H), 4.79-4.40 (m, 5H), 3.31 (s, 2H), 3.17-2.70 (m, 3H), 1.82-1.67 (m,4H), 1.08-1.03 (m, 6H); MS (APCI+) m/z 435 [M+H]⁺.

Example 55: Preparation of 3-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)butan-1-one

Step A: Following general procedure GP-H,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (14) and isovaleryl chloride wereconverted to3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)butan-1-oneas a white solid (0.065 g, 84%): mp=200-203° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.26 (d, J=94.4 Hz, 1H), 7.75-7.60 (m, 3H), 7.46-7.39 (m,1H), 4.72-4.41 (m, 5H), 3.31 (s, 2H), 3.17-2.80 (m, 2H), 2.24-2.20 (m,2H), 2.12-2.04 (m, 1H), 1.81-1.67 (m, 4H), 0.94 (d, J=13.2 Hz, 6H); MS(APCI+) m/z 449 [M+H]⁺.

Example 56: Preparation of 2,2-Dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)propan-1-one

Step A: Following general procedure GP-H,(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (14) and pivaloyl chloride were converted to2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)propan-1-oneas a white solid (0.068 g, 88%): mp=229-232° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.24 (d, J=100.5 Hz, 1H), 7.71-7.59 (m, 3H), 7.46-7.39 (m,1H), 5.26-4.55 (m, 5H), 3.31 (s, 2H), 3.17-2.74 (m, 2H), 1.80-1.68 (m,4H), 1.24 (s, 9H); MS (APCI+) m/z 449 [M+H]⁺.

Example 57: Preparation of(1-Methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1-methyl-1H-indazole-3-carboxylic acid were converted to(1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.087 g, 52%): ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d,J=7.8 Hz, 18), 7.64 (m, 1H), 7.51 (m, 1H), 7.43 (m, 3H), 7.28 (m, 2H),5.02 (m, 2H), 4.11 (s, 3H), 3.27 (m, 2H), 2.92 (m, 1H), 1.85 (m, 4H); MS(ESI+) m/z 388 [M+H]⁺.

Example 58: Preparation of(1H-Indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-indazole-3-carboxylic acid were converted to(1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.114 g, 70%): mp=175-177° C.; ¹H NMR (500 MHz, CDCl₃)δ 10.26 (bs, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.64 (m, 1H), 7.52 (m, 2H),7.43 (m, 2H), 7.28 (m, 2H), 5.00 (m, 2H), 3.28 (m, 2H), 2.98 (m, 1H),1.85 (m, 4H); MS (ESI+) m/z 374 [M+H]⁺.

Example 59: Preparation ofBenzo[d]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andbenzo[d]isoxazole-3-carboxylic acid were converted tobenzo[d]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.102 g, 63%): ¹H NMR (500 MHz, CDCl₃) δ 7.94 (d,J=7.8 Hz, 1H), 7.65 (m, 2H), 7.52 (m, 1H), 7.45 (m, 1H), 7.37 (m, 2H),4.14 (m, 1H), 4.92 (m, 1H), 4.66 (m, 1H), 3.36 (m, 2H), 2.98 (m, 1H),1.99 (m, 4H); MS (ESI+) m/z 375 [M+H]⁺.

Example 60: Preparation of(6-Methylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and ethyl6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (0.743 g, 3.76 mmol),were combined to give(6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas an off-white solid (1.35 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 8.40 (s,1H), 7.91 (m, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.52-7.43 (m, 2H), 7.31 (t,J=6.6 Hz, 1H), 7.13 (d, J=9.5 Hz, 1H), 5.30-5.23 (m, 1H), 4.96-4.91 (m,1H), 3.30-3.24 (m, 2H), 2.90 (m, 1H), 1.96-1.83 (m, 4H); MS (ESI+) m/z409 [M+H]⁺.

Step B: A mixture of(6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.030 g, 0.0734 mmol), trimethyl boroxine (0.014 g, 0.110 mmol), DPPF(0.006 g, 0.00734 mmol), K₂CO₃ (0.020 g, 0.147 mmol), 1,4-dioxane (2 mL)and H₂O (0.3 mL) was heated in sealed tube under an atmosphere of N₂ at110° C. for 5 hours. The mixture was cooled to ambient temperature,diluted with EtOAc, and solids were filtered. The filtrate wasconcentrated under reduced pressure and the residue was chromatographedover silica gel (0-3% CH₃OH in CH₂Cl₂) to give(6-methylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as an off-white solid (0.015 g, 52%): mp144-147° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.82 (d, J=9.4 Hz,1H), 7.64 (d, J=7.8 Hz, 1H), 7.53-7.44 (m, 2H), 7.30 (m, 1H), 6.96 (d,J=9.4 Hz, 18), 5.30 (m, 1H), 4.94 (m, 1H), 3.26 (m, 2H), 2.93 (m, 1H),2.59 (s, 3H), 1.89-1.77 (m, 4H); MS (ESI+) m/z 489 (M+H).

Example 61: Preparation of(6-Morpholinoimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneBPN-0004342-AA-001

Step A: A mixture of(6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.030 g, 0.0734 mmol) and morpholine (1.5 mL) was heated at 120° C. for2 hours. The mixture cooled to ambient temperature and was concentratedunder reduced pressure. The material was dissolved in CH₂Cl₂ and thesolution was washed with aqueous, saturated NaHCO₃ solution, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingresidue was chromatographed over silica gel (0-100% EtOAc in hexanes) togive(6-morpholinoimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.015 g, 44%): mp 203-205° C.; ¹H NMR (300 MHz, CDCl₃)δ 8.17 (s, 1H), 7.71 (d, J=10.0 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H),7.53-7.43 (m, 2H), 7.30 (m, 1H), 6.96 (d, J=10.0 Hz, 1H), 5.38 (m, 1H),4.93 (m, 1H), 3.85 (m, 4H), 3.50 (m, 4H), 3.24 (m, 2H), 2.88 (m, 1H),1.88-1.76 (m, 4H); MS (ESI+) m/z 460 [M+H]⁺.

Example 62: Preparation of(6-Methoxyimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of(6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.060 g, 0.147 mmol) in CH₂OH (6 mL) was added a solution of NaOCH₃ inCH₃OH (0.5 M, 2.94 mL, 1.47 mmol). The mixture was heated 70° C. for 1h, cooled to ambient temperature and evaporated. The residue wasdissolved in CH₂Cl₂ and the solution was washed with saturated NaHCO₃,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The resulting residue was chromatographed over silica gel (0-70% EtOAcin hexanes) and freeze dried to give(6-methoxyimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.015 g, 25%): mp 120-123° C.; ¹H NMR (300 MHz, CDCl₃)δ 8.24 (s, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.49 (m,2H), 7.30 (m, 1H), 6.74 (d, J=9.6 Hz, 1H), 5.38 (m, 1H), 4.93 (m, 1H),4.00 (s, 3H), 3.25 (m, 2H), 2.86 (m, 1H), 1.89-1.77 (m, 4H); MS (ESI+)m/z 405 [M+H]⁺.

Example 63: Preparation of(6-Cyclopropylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A mixture of(6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.050 g, 0.122 mmol), potassium cyclopropyltrifluoroborate (0.026 g,0.183 mmol), Pd(OAc)₂ (0.002 g, 0.0061 mmol),di-(1-adamantyl)-n-butylphosphine (0.004 g, 0.0122 mmol), and Cs₂CO₃(0.119 g, 0.366 mmol) in toluene (2 mL) and H₂O (0.2 mL) was heated at100° C. for 3 hours. The mixture was concentrated under reduced pressureand the resulting residue was chromatographed over silica gel (0-60%EtOAc in hexanes) to give(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.035 g, 69%): ¹H NMR (300 MHz, CDCl₃) δ 8.30 (s, 1H),7.78 (m, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.54-7.44 (m, 2H), 7.30 (t, J=7.8Hz, 1H), 6.88 (d, J=9.6 Hz, 1H), 5.30 (m, 1H), 4.94 (m, 1H), 3.27 (m,2H), 2.69 (m, 1H), 2.12-1.81 (m, 5H), 1.14-1.08 (m, 4H); MS (ESI+) m/z415 [M+H]⁺.

Example 64: Preparation of(6-(Pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A mixture of(6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.030 g, 0.0734 mmol) and morpholine (1.5 mL) was heated at 100° C. for3 hours. The mixture cooled to ambient temperature and was concentratedunder reduced pressure. The residue was chromatographed over silica gel(0-70% EtOAc in hexanes) to give(6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as an off-white solid (0.046 g, 85%): mp 170-171° C.; ¹H NMR(300 MHz, CDCl₃) δ 8.15 (s, 1H), 7.63 (d, J=9.3 Hz, 1H), 7.53-7.44 (m,2H), 7.30 (t, J=7.8 Hz, 1H), 6.66 (d, J=9.9 Hz, 1H), 5.42 (m, 1H), 4.93(m, 1H), 3.50 (m, 4H), 3.24 (m, 2H), 2.87 (m, 1H), 2.07-1.80 (m, 8H); MS(ESI+) m/z 444 [M+H]⁺.

Example 65: Preparation of(1H-Pyrrolo[2,3-c]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid were converted to(1H-pyrrolo[2,3-c]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.110 g, 67%): mp 214-218° C.; ¹H NMR (500MHz, DMSO-d₆) δ 11.99 (s, 1H), 8.90 (s, 1H), 8.22 (d, J=5.5 Hz, 1H),7.72-7.68 (m, 2H), 7.67-7.63 (m, 14), 7.46-7.40 (m, 1H), 7.38 (d, J=6.0Hz, 1H), 6.98 (d, J=1.0 Hz, 1H), 4.73-4.44 (m, 2H), 3.08-2.77 (m, 34),1.93-1.74 (m, 4H); ESI MS m/z 374 [M+H]⁺.

Example 66: Preparation of(1H-Pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid were converted to(1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.125 g, 77%): mp 275-278° C. decomp.; ¹HNMR (500 MHz, DMSO-d₆) δ 11.81 (s, 1H), 8.39 (dd, J=6.0, 1.5 Hz, 14),7.79 (d, J=8.5 Hz, 1H), 7.73-7.63 (m, 34), 7.46-7.41 (m, 1H), 7.19 (dd,J=8.5, 4.5 Hz, 1H), 6.93 (d, J=1.5 Hz, 1H), 4.73-4.42 (m, 2H), 3.28-2.81(m, 3H), 1.92-1.76 (m, 4H); ESI MS m/z 374 [M+H]⁺.

Example 67: Preparation of (1H-Indol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-indole-2-carboxylic acid were converted to(1H-indol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone asa white solid (0.127 g, 68%): mp 189-192° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 11.56 (s, 1H), 7.71-7.68 (m, 2H), 7.67-7.63 (m, 1H), 7.60 (d, J=8.0Hz, 1H), 7.45-7.40 (m, 2H), 7.20-7.16 (m, 1H), 7.06-7.02 (m, 1H), 6.82(dd, J=2.5, 1.0 Hz, 1H), 4.63 (d, J=12.5 Hz, 2H), 3.23-2.94 (m, 3H),1.88-1.75 (m, 4H); ESI MS m/z 373 [M+H]⁺.

Example 68: Preparation of(1H-Benzo[d]imidazol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-benzo[d]imidazole-2-carboxylic acid were converted to(1H-benzo[d]imidazol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.121 g, 67%): mp 178-185° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.11 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.71-7.60 (m, 3H),7.55 (d, J=8.5 Hz, 1H), 7.45-7.38 (m, 1H), 7.35-7.29 (m, 1H), 7.28-7.22(m, 1H), 5.83-5.77 (m, 1H), 4.79-4.73 (m, 1H), 3.35-3.27 (m, 1H),3.25-3.16 (m, 1H), 3.00-2.90 (m, 1H), 1.95-1.71 (m, 4H); ESI MS m/z 374[M+H]⁺.

Example 69: Preparation ofImidazo[1,2-b]pyridazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andimidazo[1,2-b]pyridazine-2-carboxylic acid were converted toimidazo[1,2-b]pyridazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.082 mg, 50%): mp 133-135° C.; ¹H NMR (500MHz, DMSO-d₆) δ 8.61-8.58 (m, 2H), 8.21-8.18 (m, 1H), 7.70-7.60 (m, 3H),7.44-7.39 (m, 1H), 7.33-7.29 (m, 1H), 5.15-5.06 (m, 1H), 4.77-4.67 (m,1H), 3.28-3.12 (m, 2H), 2.93-2.81 (m, 1H), 1.90-1.67 (m, 4H); ESI MS m/z375 [M+H]⁺; HPLC>99% purity (Method F).

Example 70: Preparation of(6-Methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(Trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-methyl-1N-pyrrolo[3,2-b]pyridine-2-carboxylic acid were converted to(6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.048 g, 21%): mp254-258° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.66 (br s, 1H), 8.26 (d,J=2.0 Hz, 1H), 7.72-7.68 (m, 2H), 7.67-7.62 (m, 1H), 7.58 (s, 1H),7.45-7.40 (m, 1H), 6.88 (d, J=1.0 Hz, 1H), 4.69-4.52 (m, 2H), 3.31-2.98(m, 3H), 2.41 (s, 3H), 1.19-1.78 (m, 4H); ESI MS m/z 388 [M+H]⁺.

Example 71: Preparation of(1H-Imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-imidazo[4,5-b]pyridine-2-carboxylic acid were converted to(1H-imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.037 g, 39%): mp 249-251° C.; ¹H NMR (500MHz, DMSO-d₆) δ 13.72 (br s, 0.5H), 13.38 (br s, 0.5H), 8.51-8.42 (m,1H), 8.18 (d, J=8.0 Hz, 0.5H), 7.96 (d, J=8.0 Hz, 0.5H), 7.71-7.60 (m,3H), 7.45-7.40 (m, 1H), 7.37-7.30 (m, 1H), 5.71-5.64 (m, 0.5H),5.36-5.29 (m, 0.5H), 4.78-4.70 (m, 1H), 3.38-3.27 (m, 1H), 3.27-3.16 (m,1H), 3.03-2.93 (m, 1H), 1.98-1.70 (m, 4H); ESI MS m/z 375 [M+H]⁺.

Example 72: Preparation of(6-Fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A solution of 2-bromo-5-fluoropyridin-3-amine (0.670 g, 3.51mmol) in DMF (6.0 mL) was deoxygenated with argon gas for 20 minutes. Tothe solution was added Et₂N (1.97 mL, 14.0 mmol) and pyruvic acid (0.73mL, 10.5 mmol) and the resulting mixture was deoxygenated with argon gasfor 10 minutes. Pd(OAc)₂ (0.157 g, 0.702 mmol) was added and thereaction mixture heated to 110° C. under argon atmosphere for 18 hours.The reaction was concentrated under reduced pressure and the obtainedresidue was triturated with CH₂OH (100 mL). The obtained solids werediluted in H₂O (30 mL) and 1 N HCl added until a neutral pH wasachieved. The resulting solution was extracted with EtOAc (4×30 mL) thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to yield6-fluoro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid as an off-whitesolid (0.030 g, 5%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.37 (s, 1H), 12.15(s, 1H), 8.46 (dd, J=2.7, 1.8 Hz, 1H), 7.64-7.59 (m, 1H), 7.19-7.17 (m,1H); ESI MS m/z 181 [M+H]⁺.

Step B: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-fluoro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid were converted to(6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.033 g, 54%): mp250-252° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.41 (dd, J=2.5,1.5 Hz, 1H), 7.74-7.61 (m, 4H), 7.46-7.41 (m, 1H), 6.98 (d, J 1.5 Hz,1H), 4.72-4.42 (m, 2H), 3.33-3.13 (m, 3H), 1.93-1.74 (m, 4H); ESI MS m/z392 [M+H]⁺.

Example 73: Preparation of(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and5-methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid were converted to(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (0.072 g, 63%) as a white solid: mp203-205° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.68 (s, 1H), 7.74-7.67 (m,3H), 7.67-7.62 (m, 1H), 7.45-7.40 (m, 1H), 6.81 (d, J=1.5 Hz, 1H), 6.67(d, J=9.0 Hz, 1H), 4.64-4.56 (m, 2H), 3.85 (s, 3H), 3.25-2.91 (m, 3H),1.91-1.75 (m, 4H); ESI MS m/z 404 [M+H]⁺.

Example 74: Preparation of(1-Methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: To a solution of(1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.035 g, 0.094 mmol) in DMF (0.5 mL) was added sodium hydride (60% inmineral oil, 0.006 g, 0.14 mmol) and the resulting solution stirred atambient temperature for 45 minutes. To the solution was addediodomethane (0.09 mL, 0.14 mmol) and the resulting solution was stirredat ambient temperature for 3 hours. The reaction was carefully quenchedwith H₂O (20 mL) and extracted with EtOAc (3×30 mL). The combinedorganics were washed with brine (3×10 mL) and 5% aqueous LiCl (2×10 mL),filtered, and concentrated to dryness under reduced pressure. Theresulting residue was chromatographed over silica gel (Isco CombiFlashRf unit, 12 g Redisep column, 0% to 3% CH₂OH in CH₂Cl₂ with 0.01% NH₄OH)followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 15micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) to provide(1-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.006 g, 17%): mp 159-163° C.; ¹H NMR (500MHz, CH₂OD-d₄) δ 8.30 (dd, J=5.0, 1.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H),7.58-7.49 (m, 3H), 7.31-7.26 (m, 1H), 7.23-7.20 (m, 1H), 6.74 (d, J=0.5Hz, 1H), 4.85-4.76 (m, 1H), 4.17-4.03 (m, 1H), 3.78 (s, 3H), 3.01-2.83(m, 1H), 1.89-1.65 (m, 4H); ESI MS m/z 388 [M+H]⁺.

Example 75: Preparation of(6-(1H-Imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid were converted to(6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a yellow solid (1.66 g, 64%): ¹H NMR (300MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.00 (dd, J 1.8,0.6 Hz, 1H), 7.74-7.59 (m, 3H), 7.47-7.39 (m, 1H), 7.01-6.98 (m, 1H),4.77-4.35 (m, 2H), 3.27-2.78 (m, 3H), 2.04-1.54 (m, 4H); ESI MS m/z 453[M+H]⁺.

Step B: A solution of(6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.150 g, 0.332 mmol) in DMSO (1.0 mL) was deoxygenated with argon gasfor 15 minutes.

To the solution was added imidazole (0.225 g, 3.32 mmol) and Cs₂CO₃(0.216 g, 0.664). The resulting mixture was deoxygenated with argon gasfor 15 minutes. CuI (6.3 mg, 0.033 mmol) andtrans-bis(1,2-methylamine)cyclohexane (60 □L, 0.38 mmol) were added andthe reaction vessel was sealed and heated to 130° C. for 18 hours. Thereaction mixture was cooled to ambient temperature and diluted with 1:1brine/conc. NH₄OH (15 mL). The solution was extracted with CH₂Cl₂ (4×30mL) the combined organic extracts were washed with 1:1 brine/conc. NH₄OH(4×30 mL) and concentrated. The obtained residue was purified by flashcolumn chromatography (Isco CombiFlash Rf unit, 12 g Redisep column, 0%to 10% CH₃OH in CH₂Cl₂ with 0.01% NH₄OH) to provide(6-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as an off-white solid (0.054 g, 36%): mp>270° C.; ¹H NMR (500MHz, DMSO-d₆) δ 12.11 (s, 1H), 8.71 (d, J=2.5 Hz, 1H), 8.28 (s, 1H),7.95 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.75-7.64 (m, 3H), 7.46-7.41 (m,1H), 7.15 (s, 1H), 7.03 (d. J=1.5 Hz, 1H), 4.76-4.36 (m, 2H), 3.24-2.85(m, 3H), 1.97-1.71 (m, 4H); ESI MS m/z 440 [M+H]⁺.

Example 76: Preparation of(6-Morpholino-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: A solution of(6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.150 g, 0.332 mmol) in DMSO (1.5 mL) was deoxygenated with argon gasfor 15 min. To the solution was added morpholine (0.29 mL, 3.3 mmol) andCs₂CO₃ (0.216 g, 0.664). The resulting mixture was deoxygenated withargon gas for 15 minutes. CuI (6.3 mg, 0.033 mmol) andtrans-bis(1,2-methylamine)cyclohexane (60 μL, 0.38 mmol) were added andthe reaction vessel was sealed and heated to 130° C. for 18 hours. Thereaction was cooled and deoxygenated with argon gas for 15 minutes.Additional morpholine (0.29 mL, 3.32 mmol) added and the mixturedeoxygenated for 5 minutes. Cur (0.0315 g, 0.165 mmol) was added and thevessel sealed and heated to 130° C. for 48 hours. The reaction mixturewas cooled to ambient temperature and diluted with 1:1 brine/conc. NH₄OH(15 mL). The solution was extracted with CH₂Cl₂ (3×30 mL) the combinedorganic extracts were washed with 1:1 brine/conc. NH₄OH (5×30 mL) andconcentrated under reduced pressure. The obtained residue was purifiedby flash column chromatography (Isco CombiFlash Rf unit, 24 g Redisepcolumn, 0% to 6% CH₃OH in CH₂Cl₂ with 0.01% NH₄OH) to provide(6-morpholino-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas an off-white solid (0.007 g, 4%): mp 268-272° C. decomp.; ¹H NMR (500MHz, DMSO-d₆) δ 11.48-11.47 (m, 1H), 8.33 (d, J=2.5 Hz, 1H), 7.72-7.62(m, 3H), 7.45-7.40 (m, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.84 (d, J=1.5 Hz,1H), 4.66-4.57 (m, 2H), 3.81-3.76 (m, 4H), 3.21-3.11 (m, 7H), 1.88-1.77(m, 4H); ESI MS m/z 459 [M+H]⁺; HPLC 97.8% purity (Method F).

Example 77: Preparation of(6-Chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid were converted to(6-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a light yellow solid (0.049 g, 23%): mp 258-261° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.00 (s, 1H), 8.40 (d, J=3.0 Hz, 1H), 7.86 (dd, J=2.5, 1.0Hz, 1H), 7.73-7.63 (m, 3H), 7.45-7.42 (m, 1H), 6.99 (d, J=1.5, 2.5 Hz,1H), 4.74-4.39 Cm, 2H), 3.23-2.85 (m, 3H), 1.96-1.72 (m, 4H); ESI MS m/z408 [M+H]⁺; HPLC>99% purity (Method F).

Example 78: Preparation ofBenzo[d]thiazol-2-yl-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andbenzo[d]thiazole-2-carboxylic acid were converted tobenzo[d]thiazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.059 g, 35%): mp 151-153° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.22-8.13 (m, 2H), 7.71-7.57 (m, 5H), 7.44-7.41 (m, 1H),5.40-5.37 (m, 1H), 4.71-4.68 (m, 1H), 3.99-3.21 (m, 2H), 3.01-3.03 (m,1H), 1.92-1.83 (m, 4H); ESI MS m/z 391 [M+H]⁺.

Example 79: Preparation ofBenzo[d]oxazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andbenzo[d]oxazole-2-carboxylic acid were converted tobenzo[d]oxazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.018 g, 11%): ¹H NMR (500 MHz, DMSO-d₆) δ 7.92-7.86(m, 2H), 7.71-7.41 (m, 6H), 4.70-4.67 (m, 2H), 3.80-3.35 (m, 1H),3.23-3.18 (m, 1H), 3.05-2.99 (m, 1H), 1.92-1.77 (m, 4H); ESI MS m/z 375[M+H]⁺.

Example 80z Preparation ofPyridazin-4-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andpyridazine-4-carboxylic acid were converted topyridazin-4-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone asa white solid (0.054 g, 36%): mp 159-162° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 9.36 (br s, 2H); 7.82-7.65 (m, 3H), 7.45-7.41 (m, 1H), 4.67-4.64 (m,1H), 3.53-3.51 (m, 1H), 3.28-3.21 (m, 1H), 3.13-3.09 (m, 1H), 2.93-2.87(m, 1H), 1.91-1.60 (m, 4H); ESI MS m/z 336 [M+H]⁺.

Example 81: Preparation ofImidazo[1,2-b]pyridazin-6-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andimidazo[1,2-b]pyridazine-6-carboxylic acid were converted toimidazo[1,2-b]pyridazin-6-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (0.068 g, 41%): mp 152-155° C.; ¹H NMR (500MHz, DMSO-de) δ 8.35 (s, 1H); 8.26 (d, J=9.0 Hz, 1H), 7.87 (d, J=1.0 Hz,1H), 7.71-7.65 (m, 3H), 7.43-7.40 (m, 2H), 4.69-4.66 (m, 1H), 3.89-3.86(m, 1H), 3.28-3.24 (m, 1H), 3.17-3.15 (m, 1H), 2.99-2.92 (m, 1H),1.83-1.77 (m, 3H), 1.67-1.65 (m, 1H); ESI MS m/z 375 [M+H]⁺.

Example 82: Preparation ofpyridazin-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methadone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andpyridazine-3-carboxylic acid were converted topyridazin-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone asan off-white solid (0.060 g, 41%): mp 125-127° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.32-9.30 (m, 1H); 7.94-7.84 (m, 2H), 7.71-7.64 (m, 3H),7.44-7.41 (m, 1H), 4.73-4.70 (m, 1H), 3.73-3.71 (m, 1H), 3.28-3.22 (m,1H), 3.18-3.14 (m, 1H), 2.99-2.93 (m, 1H), 1.83-1.81 (m, 3H), 1.67-1.65(m, 1H); ESI MS m/z 336 [M+H]⁺.

Example 83: Preparation of(6-Chloropyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-chloropyridazine-3-carboxylic acid were converted to(6-chloropyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.035 g, 21%): mp 170-172° C.; ¹H NMR (300 MHz,DMSO-d₆ δ 8.12-8.02 (m, 2H), 7.70-7.66 (m, 3H), 7.46-7.40 (m, 1H),4.71-4.66 (m, 1H), 3.76-3.71 (m, 1H), 3.33-3.16 (m, 2H), 3.02-2.92 (m,1H), 1.84-1.81 (m, 3H), 1.66-1.62 (m, 1H); ESI MS m/z 370 [M+H]⁺.

Example 84: Preparation of(4-Methyl-1,2,3-thiadiazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and4-methyl-1,2,3-thiadiazole-5-carboxylic acid were converted to(4-methyl-1,2,3-thiadiazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas an off-white solid (0.111 g, 71%): mp 141-143° C.; TH NMR (500 MHz,DMSO-d₆ δ 7.73-7.64 (m, 3H), 7.44-7.41 (m, 1H), 4.67-4.65 (m, 1H),3.45-3.43 (m, 1H), 3.26-3.22 (m, 1H), 3.14-3.08 (m, 1H), 2.97-2.92 (m,1H), 2.67 (s, 3H), 1.85-1.62 (m, 4H); ESI MS m/z 356 [M+H]⁺.

Example 85: Preparation of(6-Methylpyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-methylpyridazine-3-carboxylic acid were converted to(6-methylpyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.052 g, 69%): mp 144-148° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.83-7.65 (m, 5H), 7.46-7.40 (m, 1H), 4.72-4.68 (m, 1H),3.78-3.74 (m, 1H), 3.29-3.15 (m, 2H), 2.99-2.90 (m, 1H), 2.67 (s, 3H),1.83-1.78 (m, 3H), 1.66-1.62 (m, 1H); ESI MS m/z 350 [M+H]⁺.

Example 86s Preparation of(6-Methoxypyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-methoxypyridazine-3-carboxylic acid were converted to(6-methoxypyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas an off-white solid (0.047 g, 56%): mp 122-125° C.; ¹H NMR (300 MHz,DMSO-d₆ δ 7.86-7.67 (m, 4H), 7.43-7.35 (m, 2H), 4.72-4.67 (m, 1H), 4.08(s, 3H), 3.96-3.91 (m, 1H), 3.24-3.16 (m, 2H), 2.98-2.92 (m, 1H),1.81-1.64 (m, 4H); ESI MS m/z 366 [M+H]⁺.

Example 87: Preparation ofPyrazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andpyrazine-2-carboxylic acid were converted topyrazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as awhite solid (0.015 g, 19%): mp 109-111° C.; ¹H NMR (300 MHz, DMSO-d₆) δ8.91 (s, 1H), 8.76-8.70 (m, 2H), 7.71-7.65 (m, 3H), 7.45-7.42 (m, 1H),4.71-4.66 (m, 1H), 3.81-3.76 (m, 1H), 3.28-3.15 (m, 2H), 2.98-2.88 (m,1H), 1.83-1.62 (m, 4H); ESI MS m/z 336 [M+H]⁺.

Example 88: Preparation of(1H-1,2,3-Triazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and 1H-1,2,3triazole-5-carboxylic acid were converted to1H-1,2,3-triazole-5-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.019 g, 25%): mp 235-239° C. dec.; ¹H NMR (300 MHz,DMSO-d₆) δ 15.48 (br s, 1H), 8.32 (br s, 1H), 7.70-7.60 (m, 3H),7.44-7.39 (m, 1H), 4.73-4.66 (m, 28), 3.26-3.22 (m, 2H), 2.90-2.82 (m,1H), 1.85-1.62 (m, 4H); ESI MS m/z 325 [M+H]⁺.

Example 89: Preparation of(6-Chloro-2-methylimidazol[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and6-Chloro-2-methylimidazol[1,2-b]pyridazin-3-carboxylic acid wereconverted to(6-Chloro-2-methylimidazol[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone(0.052 g, 32%): mp 147-150° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d,J=9.6 Hz, 1H), 7.71-7.66 (m, 3H), 7.45-7.42 (m, 2H), 4.72-4.69 (m, 1H),3.58-3.46 (m, 1H), 3.29-3.15 (m, 2H), 3.03-2.98 (m, 1H), 2.45 (s, 3H)1.89-1.57 (m, 4H); ESI MS m/z 423 [M+H]⁺.

Example 90: Preparation of(1H-pyrazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneBPN-0004468-AA-001

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and1H-pyrazole-5-carboxylic acid were converted to(1H-pyrazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.051 g, 42%): mp=167-170° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 13.14 (α, 1H), 7.81 (q, J=1.6 Hz, 1H), 7.69-7.61 (m, 3H),7.43-7.39 (m, 1H), 6.59 (t, J=2.1 Hz, 1H), 4.87 (d, J=13.3 Hz, 1H), 4.70(d, J=12.3 Hz, 1H), 3.19-3.03 (m, 2H), 2.81 (t, J=11.7 Hz, 1H),1.81-1.66 (m, 4H); MS (APCI+) m/z 324 [M+H]⁺.

Example 91: Preparation ofImidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneBPN-0003856-AA-001

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride andimidazo[1,2-a]pyridine-2-carboxylic acid were converted toimidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.052 g, 32%): mp=130-133° C.; ¹H NMR (500 MHz, CDCl₃)δ 8.16 (d, J=7.8 Hz, 1H), 8.09 (s, 1H), 7.62 (m, 2H), 7.53 (m, 2H), 7.48(m, 1H), 7.30 (m, 1H), 6.82 (m, 1H), 5.42 (m, 1H), 4.91 (m, 1H), 3.26(m, 2H), 2.98 (m, 1H), 1.83 (m, 4H); MS (ESI+) m/z 374 [M+H]⁺.

Example 92: Preparation of4-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and4-carbamoylbenzoic acid were converted to4-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide as awhite solid (0.119 g, 72%): mp 188-190° C.; ¹H NMR (500 MHz, DMSO-d₆) δ8.05 (s, 1H), 7.94 (d, J=8.1 Hz, 2H), 7.77 (d, J=7.8 Hz, 1H), 7.67 (m,2H), 7.54 (d, J=8.1 Hz, 2H), 7.43 (m, 2H), 4.68 (m, 1H), 3.63 (m, 1H),3.18-3.11 (m, 2H), 2.86 (m, 1H), 1.82-1.63 (m, 4H); MS (ESI+) m/z 377[M+H]⁺.

Example 93: Preparation of 3-(4-(2-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide BPN-0003791-AA-001

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and3-carbamoylbenzoic acid were converted to3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide as awhite solid (0.149 g, 90%): mp 192-194° C.; ¹H NMR (500 MHz, DMSO-d₆) δ8.06 (s, 1H), 7.95 (m, 2H), 7.74 (d, J=7.9 Hz, 1H), 7.69-7.61 (m, 3H),7.54 (t, J=8.0 Hz, 1H), 7.46-7.41 (m, 2H), 4.68 (m, 1H), 3.65 (m, 1H),3.20-3.12 (m, 2H), 2.89 (m, 1H), 1.78-1.64 (m, 4H); MS (ESI+) m/z 377[M+H]⁺.

Example 94: Preparation of4-Oxo-4-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)butanoic acid

Step A: A mixture of 4-(2-(trifluoromethyl)phenyl)piperidine (5, 0.100g, 0.436 mmol) and dihydrofuran-2,5-dione (0.048 g, 0.480 mmol) inCH₂Cl₂ (8 mL) was heated at reflux for 4 hours, cooled to ambienttemperature and concentrated. The resulting residue was chromatographedover silica gel (0-30% EtOAc in hexanes) to give4-oxo-4-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)butanoic acid as awhite solid (0.134 g, 93%): mp 18-140° C.; ¹H NMR (500 MHz, CDCl₃) δ7.64 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H),7.31 (d, J=7.6 Hz, 1H), 4.81 (m, 1H), 4.01 (m, 1H), 3.22-3.17 (m, 2H),2.80-2.68 (m, 5H), 1.89 (m, 2H), 1.73-1.65 (m, 2H); MS (ESI+) m/z 330[M+H]⁺.

Example 95t Preparation of3-Oxo-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)propanoic acid

Step A: To a solution of 4-(2-(trifluoromethyl)phenyl)piperidine (5,0.130 g, 0.567 mmol) and Et₃N (0.157 mL, 1.13 mmol) in CH₂Cl₂ (10 mL)was added methyl 3-chloro-3-oxopropanoate (0.077 g, 0.567 mmol) at 0° C.The mixture was warmed to ambient temperature, stirred for 16 hours andconcentrated under reduced pressure. The residue was chromatographedover silica gel (0-40% EtOAc in hexanes) to give methyl3-oxo-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) propanoate (0.134g, 71%): ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J=7.9 Hz, 1H), 7.53 (t,J=7.5 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 4.85-4.78(m, 1H), 3.90-3.84 (m, 1H), 3.78 (s, 3H), 3.60-3.49 (m, 2H), 3.28-3.14(m, 2H), 2.75-2.65 (m, 1H), 1.89-1.64 (m, 4H); MS (ESI+) m/z 330 [M+H]⁺.

Step B: To a solution of methyl 3-oxo-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)propanoate (0.134 g, 0.407 mmol) in CH₃OH (2 mL)and THF (2 mL) was added NaOH (2 N, 2 mL). The mixture was stirred 16 h,diluted with H₂O (25 mL), and acidified with 2 N HCl to pH 4. Themixture was extracted with CH₂Cl₂ (30 mL). The extract was dried overNa₂SO₄ and evaporated to give3-oxo-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)propanoic acid as awhite solid (0.100 g, 78%): mp 112-114° C.; ¹H NMR (500 MHz, CDCl₃) δ14.24 (br s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H),7.38-7.32 (m, 2H), 4.84 (m, 1H), 3.93 (m, 1H), 3.42 (m, 2H), 3.27-3.21(m, 2H), 2.83-2.77 (m, 1H), 1.99-1.93 (m, 28), 1.76-1.66 (m, 2H); MS(ESI−) m/z 314 [M−H].

Example 96: Preparation of2-Oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)acetic acid

Step A: To a solution of 4-(2-(trifluoromethyl)phenyl)piperidine (5,0.140 g, 0.611 mmol) and Et₃N (0.171 mL, 1.22 mmol) in CH₂Cl₂ (4 mL) wasadded ethyl 2-chloro-2-oxoacetate (0.100 g, 0.733 mmol) at 0° C. Themixture was warmed to ambient temperature, stirred for 16 hours andconcentrated under reduced pressure. The residue was chromatographedover silica gel (0-25% EtOAc in hexanes) to give ethyl2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)acetate as a thickoil (0.190 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ 7.64 (d, J=7.9 Hz, 1H),7.54 (t, J=7.6 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H),4.72-4.67 (m, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.83-3.77 (m, 1H), 3.29-3.18(m, 2H), 2.84-2.75 (m, 1H), 1.92-1.67 (m, 4H), 1.39 (t, J=7.1 Hz, 3H);MS (ESI+) m/z 330 [M+H]⁺.

Step B: To a solution of ethyl2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)acetate (0.190 g,0.577 mmol) in CH₃OH (2 mL) and THF (2 mL) was added NaOH (2 N, 2 mL).The mixture was stirred 16 h, diluted with H₂O (25 mL), and acidifiedwith 2 N HCl to pH 4. The mixture was extracted with CH₂Cl₂ (30 mL). Theextract was dried over Na₂SO₄, filtered, and concentrated. The residuewas chromatographed over silica gel (0-15% CH₃OH in CH₂Cl₂) to give2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)acetic acid as awhite solid (0.035 g, 20%): mp 193-196° C.; ¹H NMR (500 MHz, DMSO-d₆) δ7.69-7.55 (m, 3H), 7.42 (d, J=7.6 Hz, 1H), 4.43 (m, 1H), 3.96 (m, 1H),3.07 (br s, 2H), 2.64 (br s, 1H), 1.69-1.55 (m, 4H); MS (ESI−) m/z 300[M−H].

Example 97: Preparation of1-(2-(4-(2-(Tert-butyl)phenyl)piperidine-1-carbonyl)pyrrolidin-1-yl)ethanone

Step A: Following general procedure GP-A2,4-(2-(tert-butyl)phenyl)piperidine and 1-acetylpyrrolidine-2-carboxylicacid were converted to1-(2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)pyrrolidin-1-yl)ethanoneas a white solid (0.048 g, 97%): mp 50-60° C.; ¹H NMR (300 MHz, CDCl₃) δ7.38-7.09 (m, 4H), 4.99-4.91 (m, 1H), 4.77 (m, 1H), 4.15-4.08 (m, 1H),3.77-3.10 (m, 4H), 2.74-2.59 (m, 1H), 2.23-1.70 (m, 10H), 1.99-1.93 (m,2H), 1.76-1.66 (m, 2H), 1.43 (s, 9H); MS (ESI+) m/z 357 [M+H]⁺.

Example 98: Preparation of(4-(2-(Tert-butyl)phenyl)piperidin-1-yl)((2R,4R)-4-hydroxypyrrolidin-2-yl)methanone

Step A: A mixture of 4-(2-(tert-butyl)phenyl)piperidine (8, 0.030 g,0.138 mmol),(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(0.038 g, 0.166 mmol), EDCI (0.032 g, 0.166 mmol), HOBt (0.022 g, 0.166mmol), Et₃N (0.058 mL, 0.414 mmol) and CH₂Cl₂ (2 mL) was stirred atambient temperature for 16 hours and then chromatographed over silicagel (0-8% CH₃OH in CH₂Cl₂ with 0.05% NH₄OH) to give (2R,4R)-tert-butyl2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate as a thick oil(0.043 g, 72%); MS (ESI+) m/z 431 [M+H]⁺.

Step B: To a solution of (2R,4R)-tert-butyl2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate(0.043 g, 0.100 mmol) in CH₂Cl₂ (1 mL) was added TFA (0.5 mL). Themixture was stirred for 4 hours, diluted with CH₂Cl₂ and washed withsaturated NaHCO₃. The organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas chromatographed over silica gel (0-5% CH₃OH in CH₂Cl₂) to give(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,4R)-4-hydroxypyrrolidin-2-yl)methanoneas a white solid (0.015 g, 45%): mp 65-75 ¹H NMR (300 MHz, CDCl₃) δ 7.38(d, J=7.4 Hz, 1H), 7.21-7.12 (m, 3H), 4.81 (m, 1H), 4.32 (m, 1H),4.18-4.08 (m, 2H), 3.57-3.43 (m, 1H), 3.24-3.15 (m, 2H), 2.94-2.88 (m,1H), 2.76-1.67 (m, 1H), 2.28-2.14 (m, 1H), 1.99-1.43 (7H), 1.44 (s, 9H);MS (ESI+) m/z 331 [M+H]⁺.

Example 99: Preparation of(4-(2-(Tert-butyl)phenyl)piperidin-1-yl)((2S,3S)-3-hydroxypyrrolidin-2-yl)methanoneBPN-0004059-AA-001

Step A: A mixture of 4-(2-(tert-butyl)phenyl)piperidine (8, 0.034 g,0.156 mmol),(2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid(0.043 g, 0.187 mmol), EDCI (0.036 g, 0.187 mmol), HOBt (0.025 g, 0.187mmol), Et₃N (0.065 mL, 0.468 mmol) and CH₂Cl₂ (2 mL) was stirred atambient temperature for 16 hours and then chromatographed over silicagel (0-5% CH₃OH in CH₂Cl₂) to give (2S,3S)-tert-butyl2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxylateas a thick oil (0.058 g, 86%); MS (ESI+) m/z 331 [M-C₅H₈O₂+H];

Step 8: To a solution of (2S,3S)-tert-butyl2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxylate(0.058 g, 0.135 mmol) in CH₂Cl₂ (2 mL) was added TFA (0.4 mL). Themixture was stirred for 2 hours, diluted with CH₂Cl₂ and washed withsaturated NaHCO₃. The organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas chromatographed over silica gel (0-8% CH₂OH in CH₂Cl₂ with 0.05%NH₄OH) to give(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2S,3S)-3-hydroxypyrrolidin-2-yl)methanone as a white solid (0.034 g, 76%): mp 60-65° C.; ¹H NMR (300MHz, CDCl₃) δ 7.36 (d, J=7.1 Hz, 1H), 7.20-7.11 (m, 3H), 4.78 (m, 1H),4.40-4.31 (m, 2H), 3.90 (m, 1H), 3.50-3.43 (m, 1H), 3.28-3.02 (m, 3H),2.76-2.63 (m, 1H), 2.44 (br s, 2H), 2.02-1.64 (m, 6H), 1.44 (s, 9H); MS(ESI+) m/z 331 [M+H]⁺.

Example 100: Preparation of(4-(2-(tert-butyl)phenyl)piperidin-1-yl)(1,1-dioxidotetrahydrothiophen-2-yl)methanone

Step A: A mixture of 4-(2-(tert-butyl)phenyl)piperidine (8, 0.030 g,0.138 mmol), tetrahydrothiophene-2-carboxylic acid (0.022 g, 0.166mmol), EDCI (0.032 g, 0.166 mmol), HOBt (0.022 g, 0.166 mmol), Et₃N(0.058 mL, 0.414 mmol) and CH₂Cl₂ (2 mL) was stirred at ambienttemperature for 16 hours and then chromatographed over silica gel (0-3%CH₃OH in CH₂Cl₂) to give(4-(2-(tert-butyl)phenyl)piperidin-1-yl)(tetrahydrothiophen-2-yl)methanoneas a thick oil (0.043 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ 7.36 (d, J=7.7Hz, 1H), 7.27-7.11 (m, 3H), 4.82-4.77 (m, 1H), 4.13-4.01 (m, 2H),3.48-3.40 (m, 1H), 3.18-2.84 (m, 3H), 2.71-2.48 (m, 2H), 2.38-2.26 (m,1H), 2.12-1.64 (m, 6H), 1.43 (s, 9H); MS (ESI+) m/z 332 [M+H]⁺.

Step B: To a solution of(4-(2-(tert-butyl)phenyl)piperidin-1-yl)(tetrahydrothiophen-2-yl)methanone(0.043 g, 0.130 mmol) in CH₃CN (3 mL) and H₂O (1.5 mL) was added Oxone(0.320 g, 0.520 mmol). The mixture was stirred for 48 hours, dilutedwith EtOAc and washed with aqueous, saturated NaHCO₃ solution. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was chromatographedover silica gel (0-50% EtOAc in hexanes) to give(4-(2-(tert-butyl)phenyl)piperidin-1-yl)(1,1-dioxidotetrahydrothiophen-2-yl)methanoneas a white solid (0.046 g, 98%): mp 80-84° C.; ¹H NMR (300 MHz, CDCl₃) δ7.39-7.09 (m, 4H), 4.90-4.78 (m, 1H), 4.29-4.20 (m, 2H), 3.55-3.08 (m,4H), 2.94-2.66 (m, 2H), 2.47-1.64 (m, 7H), 1.43 (s, 9H); MS (ESI+) m/z364 [M+H]⁺.

Example 101: Preparation of2-(2-Hydroxyphenyl)-1-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethanone

Step A: Following general procedure GP-A2,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and2-(2-hydroxyphenyl)acetic acid were converted to2-(2-hydroxyphenyl)-1-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethanoneas a red foam (0.375 g, 79%): mp No clear melt; ¹H NMR (500 MHz, CDCl₃)δ 9.81 (s, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.50-7.47 (m, 1H), 7.34-7.26 (m,2H), 7.22-7.18 (m, 1H), 7.05-7.00 (m, 2H), 6.86-6.80 (m, 1H), 4.81 (d,J=13.5 Hz, 1H), 4.31 (d, J=13.5 Hz, 1H), 3.80 (s, 2H), 3.34-3.27 (m,1H), 3.21-3.16 (m, 1H), 2.72-2.67 (m, 1H), 1.95-1.83 (m, 2H); 1.67-1.58(m, 2H); ESI MS m/z 364 [M+H]⁺.

Example 102: Preparation of 2-(2-Oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl)phenylsulfamate

Step A: A solution of2-(2-hydroxyphenyl)-1-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethanone(0.080 g, 0.22 mmol) in THF (1 mL) was added dropwise to a suspension ofsodium hydride (60% in mineral oil) (0.010 g, 0.25 mmol) in THF (2 mL)stirring at ambient temperature under a N₂ atmosphere. After 1 hour, thereaction was cooled to 0° C., and a solution of sulfamoyl chloride inTHF (1 mL) was added dropwise. The reaction was stirred at 0° C. for 1hour, quenched with H₂O, extracted with EtOAc (3×10 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The resulting residuewas chromatographed over silica gel (Isco CombiFlash Companion unit, 12g Redisep column, 0% to 100% EtOAc in hexanes) to give2-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl) phenylsulfamate as a white powder (0.048 g, 49%): mp 170-173° C.; ¹H NMR (500MHz, DMSO-d₆) δ 8.07 (s, 2H), 7.68-7.55 (m, 2H), 7.43-7.40 (m, 1H),7.35-7.28 (m, 5H), 4.58 (d, J=13.0 Hz, 1H), 4.04 (d, J=13.5 Hz, 1H),3.88-3.76 (m, 2H), 3.18-3.07 (m, 2H), 2.69-2.63 (m, 1H), 1.71-1.58 (m,4H); ESI MS m/z 443 [M+H]⁺.

Example 103: Preparation of(3-Methyloxetan-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

Step A: Following general procedure GP-A1,4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride and3-methyloxetane-3-carboxylic acid were converted to(3-methyloxetan-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.071 g, 50%): mp=100-102° C.; ¹H NMR (500 MHz, CDCl₃)δ 7.56 (d, J=7.8 Hz, 1H), 7.54 (m, 1H), 7.40 (m, 1H), 7.33 (m, 1H), 5.03(m, 2H), 4.77 (m, 1H), 4.35 (m, 2H), 3.17 (m, 3H), 2.60 (m, 1H), 1.88(m, 2H), 1.71 (m, 4H), 1.54 (m, 1H); MS (ESI+) m/z 328 [M+H]⁺.

Example 104:3-(4-(2-(Trifluoromethyl)phenyl)piperadine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile

Step A: To a solution of ethyl6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.365 g, 1.35mmol) in THF (15 mL) was added a solution of lithium hydroxide hydrate(0.057 g, 1.35 mmol) in water (5 mL). The mixture was stirred for 20minutes, acidified with 2 N HCl to pH 6 and concentrated under reducedpressure. To the residue were added4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (0.359 g, 1.35mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (898 g, 2.03 mmol), N,N-diisopropylethylamine (0.523g, 4.05 mmol), and DMF (10 mL). The mixture was stirred at ambienttemperature for 16 h, was diluted with water, and extracted with EtOAc(120 mL). The extract was washed with brine (2×120 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The resulting residuewas chromatographed over silica gel (0-60% EtOAc in hexanes) to give(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneas a white solid (0.516 g, 84%): ¹H NMR (300 MHz, CDCl₃) δ 9.38 (m, 1H),7.78 (dd, J=9.6, 0.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.55-7.44 (m, 3H),7.32 (t, J=7.7 Hz, 1H), 5.72-5.67 (m, 1H), 5.00-4.94 (m, 1H), 3.39-3.30(m, 2H), 3.03-2.93 (m, 1H), 2.01-1.81 (m, 4H); MS (ESI+) m/z 453 (M+H).

Step B: A mixture of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (0.080 g, 0.176mmol), zinc cyanide (0.041 g, 0.352 mmol), palladiumtetrakis(triphenylphosphine) (0.020 g, 0.0176 mmol), and DMF (1 mL) washeated under microwave irradiation at 130° C. for 30 min. After coolingto ambient temperature, the mixture was diluted with CH₂Cl₂ (30 mL),washed with brine (2×30 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue waschromatographed over silica gel (0-40% EtOAc in hexanes) to give3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (0.063 g, 87%): ¹H NMR(300 MHz, CDCl₃) δ9.72 (m, 1H), 7.97 (dd, J=9.5, 1.0 Hz, 1H), 7.66 (d,J=7.9 Hz, 1H), 7.55-7.42 (m, 3H), 7.33 (t, J=7.6 Hz, 1H), 5.74-5.69 (m,1H), 5.00-4.95 (m, 1H), 3.42-3.33 (m, 2H), 3.05-2.95 (m, 1H), 2.06-1.81(m, 4H); MS (ESI+) m/z 400 (M+H).

Example 105: RPM binding of Piperidine Compounds

The compounds listed in Table 1 (Compounds 15-96 and 98-129) were testedin two in vitro assays, RBP4 binding (SPA) and retinol-dependentRBP4-TTR interaction (HTRF) (FIG. 8-15). The compounds binded to RBP4and/or antagonized retinol-dependent RBP4-TTR interaction. This activityindicates that the compounds reduce the levels of serum RBP4 andretinol.

TABLE 1 # Structure 15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

70

73

74

75

76

77

78

79

80

81

82

83

84

85

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

Example 105: RPB4 Binding of Additional Piperidine Compounds

An additional aspect of the invention provides analogs of the compoundsof Table 1 that are active as RBP4 antagonists. The analogs of Compounds15-129 described herein analogously bind to RBP4 and antagonizeretinol-dependent RBP4-TTR interaction.

Additional piperidine compounds, which are analogs of those described inTable 1, are tested in two in vitro assays, RBP4 binding (SPA) andretinol-dependent RBP4-TTR interaction (HTRF). These piperidinecompounds bind to RBP4 and antagonize retinol-dependent RBP4-TTRinteraction. This activity indicates that the compounds reduce the levelof serum RBP4 and retinol.

Example 106: Efficacy in a Mammalian Model

The effectiveness of the compounds listed in Table 1 are tested inwild-type and Abca4−/− mice. The Abca4−/− mouse model manifestsaccelerated accumulation of lipofuscin in the RPE and is considered apre-clinical efficacy model for a drug reducing lipofuscin accumulation.Compounds are orally dosed for 3 weeks at 30 mg/kg. There is a reductionin the serum RBP4 level in treated animals. The levels of A2E/isoA2E andother bisretinoids are reduced in treated mice. The levels of A2-DHP-PEand atRAL di-PE are also reduced.

The effectiveness of additional piperidine compounds, which are analogsof those described in Table 1, are tested in wild-type and Abca4−/−mice. The Abca4−/− mouse model manifests accelerated accumulation oflipofuscin in the RPE and is considered a pre-clinical efficacy modelfor a drug reducing lipofuscin accumulation. Compounds are orally dosedfor 3 weeks at 30 mg/kg. There is a reduction in the serum RBP4 level intreated animals. The levels of A2E/isoA2E and other bisretinoids arereduced in treated mice. The levels of A2-DHP-PE and atRAL di-PE arealso reduced.

Discussion

Age-related macular degeneration (AMD) is the leading cause of blindnessin developed countries. Its prevalence is higher than that ofAlzheimer's disease. There is no treatment for the most common dry formof AMD. Dry AMD is triggered by abnormalities in the retinal pigmentepithelium (RPE) that lies beneath the photoreceptor cells and providescritical metabolic support to these light-sensing cells. RPE dysfunctioninduces secondary degeneration of photoreceptors in the central part ofthe retina called the macula. Experimental data indicate that highlevels of lipofuscin induce degeneration of RPE and the adjacentphotoreceptors in atrophic AMD retinas. In addition to AMD, dramaticaccumulation of lipofuscin is the hallmark of Stargardt's disease(STGD), an inherited form of juvenile onset macular degeneration. Themajor cytotoxic component of RPE lipofuscin is a pyridinium bisretinoidA2E. A2E formation occurs in the retina in a non-enzymatic manner andcan be considered a by-product of a properly functioning visual cycle.Given the established cytotoxic affects of A2E on RPE andphotoreceptors, inhibition of A2E formation could lead to delay invisual loss in patients with dry AMD and STGD. It was suggested thatsmall molecule visual cycle inhibitors may reduce the formation of A2Ein the retina and prolong RPE and photoreceptor survival in patientswith dry AMD and STGD. Rates of the visual cycle and A2E production inthe retina depend on the influx of all-trans retinol from serum to theRPE. RPE retinol uptake depends on serum retinol concentrations.Pharmacological downregulation of serum retinol is a valid treatmentstrategy for dry AMD and STGD. Serum retinol is maintained incirculation as a tertiary complex with retinol-binding protein (RBP4)and transthyretin (TTR). Without interacting with TTR, the RBP4-retinolcomplex is rapidly cleared due to glomerular filtration. Retinol bindingto RBP4 is required for formation of the RBP4-TTR complex; apo-RBP4 doesnot interact with TTR. Importantly, the retinol-binding site on RBP4 issterically proximal to the interface mediating the RBP4-TTR interaction.Without wishing to be bound by any scientific theory, the data hereinshow that small molecule RBP4 antagonists displacing retinol from RBP4and disrupting the RBP4-TTR interaction will reduce serum retinolconcentration, inhibit retinol uptake into the retina and act asindirect visual cycle inhibitors reducing formation of cytotoxic A2E.

Serum RBP4 as a Drug Target for Pharmacological Inhibition of the VisualCycle

As rates of the visual cycle and A2E production in the retina depend onthe influx of all-trans retinol from serum to the RPE (FIG. 4), it hasbeen suggested that partial pharmacological down-regulation of serumretinol may represent a target area in dry AMD treatment (11). Serumretinol is bound to retinol-binding protein (RBP4) and maintained incirculation as a tertiary complex with RBP4 and transthyretin (TTR)(FIG. 5). Without interacting with TTR, the RBP4-retinol complex israpidly cleared from circulation due to glomerular filtration.Additionally, formation of the RBP4-TTR-retinol complex is required forreceptor-mediated all-trans retinol uptake from serum to the retina.

Without wishing to be bound by any scientific theory, visual cycleinhibitors may reduce the formation of toxic bisretinoids and prolongRPE and photoreceptor survival in dry AMD. Rates of the visual cycle andA2E production depend on the influx of all-trans retinol from serum tothe RPE. Formation of the tertiary retinol-binding protein 4(RBP4)-transthyretin (TTR)-retinol complex in serum is required forretinol uptake from circulation to the RPE. Retinol-binding site on RBP4is sterically proximal to the interface mediating the RBP4-TTRinteraction. RBP4 antagonists that compete with serum retinol forbinding to RBP4 while blocking the RBP4-TTR interaction would reduceserum retinol, slow down the visual cycle, and inhibit formation ofcytotoxic bisretinoids.

RBP4 represents an attractive drug target for indirect pharmacologicalinhibition of the visual cycle and A2E formation. The retinol-bindingsite on RBP4 is sterically proximal to the interface mediating theRBP4-TTR interaction. Retinal antagonists competing with serum retinolfor binding to RBP4 while blocking the RBP4-TTR interaction would reduceserum RBP4 and retinol levels which would lead to reduced uptake ofretinol to the retina. The outcome would be visual cycle inhibition withsubsequent reduction in the A2E synthesis.

A synthetic retinoid called fenretinide [N-(4-hydroxy-phenyl)retinamide,4HRP] (FIG. 6) previously considered as a cancer treatment (29) wasfound to bind to RBP4, displace all-trans retinol from RBP4 (13), anddisrupt the RBP4-TTR interaction (13,14).

Fenretinide was shown to reduce serum RBP4 and retinol (15), inhibitocular all-trans retinol uptake and slow down the visual cycle (11).Importantly, fenretinide administration reduced A2E production in ananimal model of excessive bisretinoid accumulation, Abca4−/− mice (11).Pre-clinical experiments with fenretinide validated RBP4 as a drugtarget for dry AMD. However, fenretinide is non-selective and toxic.Independent of its activity as an antagonist of retinol binding to RBP4,fenretinide is an extremely active inducer of apoptosis in many celltypes (16-19), including the retinal pigment epithelium cells (20). Ithas been suggested that fenretinide's adverse effects are mediated byits action as a ligand of a nuclear receptor RAR (21-24). Additionally,similar to other retinoids, fenretinide is reported to stimulateformation of hemangiosarcomas in mice. Moreover, fenretinide isteratogenic, which makes its use problematic in Stargardt diseasepatients of childbearing age.

As fenretinide's safety profile may be incompatible with long-termdosing in individuals with blinding but non-life threatening conditions,identification of new classes of RBP4 antagonists is of significantimportance. The compounds of the present invention displace retinal fromRBP4, disrupt retinol-induced RBP4-TTR interaction, and reduce serumREBP4 levels. The compounds of the present invention inhibit bisretinoidaccumulation in the Abca4−/− mouse model of excessive lipofuscinogenesiswhich indicates usefulness a treatment for dry AMD and Stargardtdisease.

The present invention relates to small molecules for treatment ofmacular degeneration and Stargardt Disease. Disclosed herein is theophthalmic use of the small molecules as non-retinoid RBP4 antagonists.Compounds 15-110 have been shown to bind RBP4 in vitro and/or toantagonize RBP4-TTR interaction in vitro at biologically significantconcentrations. Additional compounds described herein, which are analogsof Compounds 15-110 analogously bind RBP4 in vitro and antagonizeRBP4-TTR interaction in vitro at biologically significantconcentrations.

Currently, there is no FDA-approved treatment for dry AMD or Stargardtdisease, which affects millions of patients. An over the counter, nonFDA-approved cocktail of antioxidant vitamins and zinc (AREDS formula)is claimed to be beneficial in a subset of dry AMD patients. There areno treatments for Stargardt disease. The present invention identifiednon-retinoid RBP4 antagonists that are useful for the treatment of dryAMD and other conditions characterized by excessive accumulation oflipofuscin. Without wishing to be bound by any scientific theory, asaccumulation of lipofuscin seems to be a direct cause of RPE andphotoreceptor demise in AMD and STGD retina, the compounds describedherein are disease-modifying agents since they directly address the rootcause of these diseases. The present invention provides novel methods oftreatment that will preserve vision in AMD and Stargardt diseasepatients, and patients' suffering from conditions characterized byexcessive accumulation of lipofuscin.

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What is claimed is:
 1. A method for treating a disease characterized byexcessive lipofuscin accumulation in the retina in a mammal afflictedtherewith comprising administering to the mammal an effective amount ofa compound having the structure:

R₁, R₂, R₃, and R₄, are each independently H, halogen, CF₃ or C₁-C₄alkyl, and wherein R₅ is CF₃; R₆ is H, OH, or halogen; B is asubstituted or unsubstituted pyridazine, pyrimidine, pyrazine, or B hasthe structure:

wherein n is 1; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁ and Y₄ are eachCH₂; and one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₃ is O, SO₂, orN—R₁₀, wherein R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃, SO₂—(C₁-C₄alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl)-CF₃, C(O)—(C₁-C₄alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl),C(O)—N(C₁-C₄ alkyl)₂, C₁-C₄ alkyl)-C(O)OH, or oxetane; or B has thestructure:

wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and Y₁, Y₂, Y₃ and Y₄ are eachindependently CR₈ or N, wherein each R₈ is independently H, halogen,C₁-C₄ alkyl, C₁-C₄ cycloalkyl, O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂,C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN, or CF₃; or B has thestructure:

wherein Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein eachR₈ is independently H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, O—(C₁-C₄alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃NHC(O)—N(CH₃)₂, CN, orCF₃; and wherein the disease characterized by excessive lipofuscinaccumulation in the retina is Age-Related Macular Degeneration, dryAge-Related Macular Degeneration, Geographic atrophy, Stargardt Disease,Best disease, adult vitelliform maculopathy, or Stargardt-like maculardystrophy; or a pharmaceutically acceptable salt thereof.
 2. The methodof claim 1, wherein the disease characterized by excessive lipofuscinaccumulation in the retina is Age-Related Macular Degeneration.
 3. Themethod of claim 1, wherein the compound has the structure:


4. A method of lowering the serum or plasma concentration of RBP4 in amammal comprising administering to the mammal an effective amount of acompound having the structure:

R₁, R₂, R₃, and R₄, are each independently H, halogen, CF₃ or C₁-C₆alkyl, and wherein R₅ is CF₃; R₆ is H, OH, or halogen; B is asubstituted or unsubstituted pyrimidine, pyridazine, pyrazine, or B hasthe structure:

wherein n is 1; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁ and Y₄ are eachCH₂; and one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₃ is O, SO₂, orN—R₁₀, wherein R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃, SO₂—(C₁-C₄alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl)-CF₃, C(O)—(C₁-C₄alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl),C(O)—N(C₁-C₄ alkyl)₂, C₁-C₄ alkyl)-C(O)OH, or oxetane; or B has thestructure:

wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and Y₁, Y₂, Y₃ and Y₄ are eachindependently CR₈ or N, wherein each R₈ is independently H, halogen,C₁-C₄ alkyl, C₁-C₄ cycloalkyl, O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂,C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN, or CF₃; or B has thestructure:

wherein Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein eachR₈ is independently H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, O—(C₁-C₄alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃NHC(O)—N(CH₃)₂, CN, orCF₃; or a pharmaceutically acceptable salt thereof.
 5. The method ofclaim 4, wherein B has the structure:

wherein n is 1; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁ and Y₄ are eachCH₂; and one of Y₂ or Y₃ is CH₂ and the other of Y₂ or Y₃ is O, SO₂, orN—R₁₀, wherein R₁₀ is H, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, (C₁-C₄alkyl)-CF₃, (C₁-C₄ alkyl)-OCH₃, (C₁-C₄ alkyl)-halogen, SO₂—(C₁-C₄alkyl), SO₂—(C₁-C₄ alkyl)-CF₃, SO₂—(C₁-C₄ alkyl)-OCH₃, SO₂—(C₁-C₄alkyl)-halogen, C(O)—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl)-CF₃, C(O)—(C₁-C₄alkyl)-OCH₃, C(O)—(C₁-C₄ alkyl)-halogen, C(O)—NH—(C₁-C₄ alkyl),C(O)—N(C₁-C₄ alkyl)₂, (C₁-C₄ alkyl)-C(O)OH, or oxetane.
 6. The method ofclaim 5, wherein B has the structure:


7. The method of claim 6, wherein B has the structure:

wherein n is 1; R₇ is H, C₁-C₄ alkyl, or oxetane; Y₁ and Y₄ are each CH₂or C(CH₃)₂; and one of Y₂ or Y₃ is CH₂, and the other of Y₂ or Y₃ isN—R₁₀; and R₁₀ is C(O)—CH₃, C(O)—CH₂CH₃, C(O)—CH₂CH₂CH₃, C(O)—CH(CH₃)₂,C(O)—CH₂CH(CH₃)₂, C(O)-t-Bu, C(O) CH₂OCH₃, C(O) CH₂CF₃, C(O)—CH₂Cl,C(O)—CH₂F, C(O)—CH₂CH₂OCH₃, C(O)—CH₂CH₂CF₃, C(O)—CH₂CH₂Cl, C(O)—CH₂CH₂F,


8. The method of claim 4, wherein B has the structure:

wherein R₇ is H, C₁-C₄ alkyl, or oxetane; and Y₁, Y₂, Y₃ and Y₄ are eachindependently CR₈ or N, wherein each R₈ is independently H, halogen,C₁-C₄ alkyl, C₁-C₄ cycloalkyl, O—(C₁-C₄ alkyl), C(O)OH, C(O)—NH₂,C(O)—N(CH₃)₂, C(O)—NHCH₃, NHC(O)—N(CH₃)₂, CN, or CF₃.
 9. The method ofclaim 4, wherein B has the structure:

wherein Y₁, Y₂, Y₃ and Y₄ are each independently CR₈ or N, wherein eachR₈ is independently H, halogen, C₁-C₄ alkyl, C₁-C₄ cycloalkyl, O—(C₁-C₄alkyl), C(O)OH, C(O)—NH₂, C(O)—N(CH₃)₂, C(O)—NHCH₃NHC(O)—N(CH₃)₂, CN, orCF₃.
 10. The method of claim 4, wherein B is pyridazine, pyrazine, orpyrimidine.
 11. The method of claim 10, wherein B has the structure:

wherein R₁₉ is H, halogen CN, CF₃, OH, NH₂, C₁-C₄ alkyl, C₃-C₆cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂, C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄alkyl)₂, C(O)OH, C(O)O(C₁-C₄ alkyl), C(O) (C₁-C₄ alkyl),C(O)NH(SO₂)—(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₃-C₆ cycloalkyl),C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₄ alkyl), NHC(O)—N(C₁-C₄alkyl)₂, SO₂—(C₁-C₄ alkyl), or tetrazole.
 12. The method of claim 10,wherein B has the structure:

wherein R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are each independently H, halogen,CN, CF₃, OH, NH₂, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl),C(O)NH₂, C(O)NH(C₁-C₁₀ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₁₀alkyl), C(O) (C₁-C₁₀ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl),C(O)NH(SO₂)—(C₃-C₆ cycloalkyl), C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂,NHC(O)—NH(C₁-C₁₀ alkyl), NHC(O)—N(C₁-C₄ alkyl)₂, SO₂—(C₁-C₁₀ alkyl), orB has the structure:

wherein R₂₁, R₂₂, R₂₄, and R₂₅ are each independently H, halogen, OH,NH₂, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, O(C₁-C₄ alkyl), C(O)NH₂,C(O)NH(C₁-C₄ alkyl), C(O)N(C₁-C₄ alkyl)₂, C(O)OH, C(O)O(C₁-C₄ alkyl),C(O) (C₁-C₄ alkyl), C(O)NH(SO₂)—(C₁-C₄ alkyl), C(O)NH(SO₂)—(C₃-C₆cycloalkyl), C(O)NH(SO₂)-(aryl), O(SO₂)—NH₂, NHC(O)—NH(C₁-C₄ alkyl),NHC(O)—N(C₁-C₄ alkyl)₂, or SO₂—(C₁-C₄ alkyl).
 13. The method of claim12, wherein B has the structure:


14. The method of claim 4, wherein the compound is administered to themammal intravenously, intravitreally, or orally.
 15. The method of claim4, wherein the compound is administered in an oral dosage form as atablet, capsule, or liquid suspension.
 16. A method for lowering theserum or plasma concentration of RBP4 in a mammal comprisingadministering to the mammal an effective amount of a compound having thestructure:

or a pharmaceutically acceptable salt thereof.
 17. The method of claim1, wherein the disease characterized by excessive lipofuscinaccumulation in the retina is dry Age-Related Macular Degeneration. 18.The method of claim 1, wherein the disease characterized by excessivelipofuscin accumulation in the retina is Geographic atrophy.
 19. Themethod of claim 1, wherein the disease characterized by excessivelipofuscin accumulation in the retina is Stargardt Disease or Bestdisease.
 20. The method of claim 1, wherein the disease characterized byexcessive lipofuscin accumulation in the retina is adult vitelliformmaculopathy or Stargardt-like macular dystrophy.